\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{A hypothesis for pathobiology and treatment of COVID-19: the centrality
of ACE1/ACE2 imbalance}



\author[1]{Krishna Sriram}%
\author[2]{Paul Insel}%
\affil[1]{University of California San Diego}%
\affil[2]{UCSD}%


\vspace{-1em}



  
  \date{June 02, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Angiotensin converting enzyme-2 (ACE2) is the receptor for the
coronavirus SARS-CoV-2, which causes COVID-19. We propose the following
hypothesis: Imbalance in the action of ACE1- and ACE2-derived peptides,
thereby enhancing Angiotensin-II (ANG II) signaling, a primary driver of
COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of
SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of ANG II to ANG
peptides that counteract pathophysiological effects of ACE1-generated
ANGII. This hypothesis suggests several approaches to treat COVID-19 by
restoring ACE1/ACE2 balance: 1) ANG II receptor blockers (ARBs); 2) ACE1
inhibitors (ACEIs); 3) Agonists of receptors activated by ACE2-derived
peptides {[}e.g., ANG (1-7), which activates MAS1{]}; 4) Recombinant
human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2
imbalance is predicted to blunt COVID-19-associated morbidity and
mortality, especially in vulnerable patients. Importantly, approved ARBs
and ACEIs can be rapidly repurposed to test their efficacy in treating
COVID-19.%
\end{abstract}%



\sloppy


\emph{Abbreviations}

ACE: Angiotensin Converting Enzyme; ANG: Angiotensin; ACEI: ACE
Inhibitor; ARB: Angiotensin Receptor Blocker; ALI: Acute Lung Injury;
ARDS: Acute Respiratory Distress Syndrome; PK: Pharmacokinetics; PD:
Pharmacodynamics; AGTR1: Angiotensin II Receptor 1; EMT:
Epithelial-to-Mesenchymal transition; RAS: Renin-Angiotensin Signaling;
ROS: Reactive oxygen species



\textbf{Introduction}

The SARS-CoV-2 virus infects human cells by first binding via its S
protein to its receptor: Angiotensin Converting Enzyme 2 (ACE2), a 120
kDa integral membrane glycoprotein on the surface of cells in the lungs,
heart, kidneys, and intestine (Wan et al., 2020; Zhang et al., 2020;
Zhou et al., 2020a; Hamming et al., 2004). Binding of SARS coronaviruses
to ACE2 is followed by fusion of the viral and plasma membranes,
endocytosis and cellular infection of the virus (Inoue at al., 2007; He
et al., 2020). ACE2 expression in respiratory epithelium is important in
the pathobiology of COVID-19 (Xu et al., 2020a). The infection typically
begins in epithelia in the upper respiratory tract, before spreading to
alveoli in the lungs (Xu et al., 2020a; Zhou et al., 2020a), pathologic
events that are more severe in patients with compromised immune response
or ability to combat the spread of infection (Rothan \& Byrareddy,
2020). COVID-19 typically (in 80\% of patients) causes mild symptoms, Wu
\& McGoogan, 2020) but severe morbidity in a subset of patients,
requiring hospitalization, intensive care and in some cases, death.
Increased morbidity and mortality occur in patients with comorbidities,
especially ones associated with aging, including hypertension, cardiac
disease, diabetes, chronic lung disease, and compromised immunity (Zhou
et al., 2020a; Wu \& McGoogan, 2020). Many strategies, are being pursued
in response to the urgent need for effective therapies of COVID-19
(e.g., Stebbing et al., 2020; Gautret et al., 2020).

The SARS-CoV-2 virus shares many characteristics with the SARS-CoV-1
coronavirus, which caused a pandemic in 2002-2003 (He et al., 2020; Wan
et al., 2020). Common features include \textasciitilde{}80\% shared
sequence identity in their viral genomes (He et al., 2020), the range of
tissues that are infected, mortality from acute respiratory distress
syndrome (ARDS) and their cellular receptor: ACE2 (Wan et al., 2020;
Zhang et al., 2020; Zhou et al., 2020a; Zhou et al., 2020b). Compared to
SAR-COV-1, SARS-CoV-2 has \textasciitilde{}4-fold higher affinity for
ACE2 (Walls et al., 2020). Due to their similarities, information
related to SARS-CoV-1 can aid in development of hypotheses for treatment
of SARS-CoV2, including the repurposing of pharmacological agents
approved for use in humans.

\textbf{How does SARS-CoV-2 infection cause pathology?}

Based on published data for both SARS viruses, we propose a
pathophysiologic chain of events for COVID-19 (\textbf{Figure 1} ).
Central to this mechanism is angiotensin (ANG II) signaling, which we
elaborate in sections below.

SARS-CoV-2 infection typically begins in the upper respiratory tract by
exposure to the virus in aerosolized droplets or from fomites (Bar-On et
al., 2020). Oral epithelial cells and other respiratory tract areas have
substantial expression of ACE2, explaining their susceptibility to viral
entry (Xu et al., 2020a; Zhou et al., 2020a). The virus spreads into the
lower respiratory tract (the lungs) where epithelial cells, in
particular type-2 pneumocytes, express ACE2 (Hamming et al., 2004;
Mossel et al., 2008; Tian et al., 2020; Zhang et al, 2020). Infection in
the lungs, and especially damage to the alveolae, is a primary cause of
morbidity in COVID-19 (He et al., 2020; Zhou et al., 2020a; Zhou et al.,
2020b). In susceptible patients, lesions from viral infection and entry
of fluid into alveolar spaces induce respiratory distress. Pulmonary
lesions appear to be a hallmark and diagnostic feature of COVID-19 (Pan
et al., 2020). Certain patients have severe inflammation and cytokine
storm, with overwhelming immune activation that attacks the host (Qin et
al., 2020). These events can produce respiratory failure and death,
especially if critical care support and mechanical ventilation are
unavailable and may ultimately be associated with multiple organ failure
and death (Du et al, 2020). The pulmonary pathobiology in COVID-19 is
akin to what occurred with SARS-1 infection (Channappanavar \& Perlman,
2017).

In addition to pulmonary injury, COVID-19 can cause cardiac
complications. Most notable is myocarditis from viral infection of the
myocardium, perhaps facilitated by ACE2 on cardiac myocytes (Sun et al.,
2020; Chen et al., 2020). Myocardial infection, myocarditis and
cardiomyopathy occurred with SARS-1 infection (Oudit et al., 2009) but
data for their frequency in COVID-19 are still emerging. Cardiac injury
in COVID-19 patients likely occurs from at least two mechanisms: a)
cytokine release (``storm'') associated with inflammation in the lung
(Pedersen \& Ho, 2020) that affects the heart and b) infection of the
myocardium, most likely via viremia (Huang et al., 2020; Kam et al.,
2020). In SARS-1, a strong association was noted between circulating
viral loads and disease severity (Hung et al., 2004). This finding
suggests that viremia results from alveolar damage and access of the
virus to the capillary network in the lung, which can occur in more
severe cases. The stage of illness during which viremia occurs in
COVID-19 and if viremia correlates with severity/injury are not as-yet
well-defined.

SARS-1 and COVID-19 can affect other tissues. A symptom of COVID-19 is
gastric distress, which can occur prior to pulmonary symptoms (Rothan \&
Byrareddy, 2020; Gu et al., 2020). Fecal transmission of SARS-CoV-2 has
also been documented (Gu et al., 2020), which confirms the presence of
the virus in the gastrointestinal (GI) tract, a site in which ACE2 is
expressed (Hamming et al., 2004). The spread of infection to the GI
tract may result from viremia or from the mouth and upper respiratory
tract, suggesting that the virus survives passage through the stomach.
COVID-19 can involve other ACE2-expressing tissues, including the
kidneys (Naicker et al., 2020).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

The primary causes of COVID-19 morbidity and mortality are: 1) lung
injury with associated respiratory distress (and accompanying cytokine
storm) and 2) heart failure or other cardiac dysfunction (Guo et al.,
2020; He et al., 2020; Zhou et al., 2020a; Zhou et al., 2020b).
Therapeutic strategies for COVID-19 seek to prevent/slow viral infection
or mitigate injury from the infection. In view of the apparent lack of
success thus far with antiviral therapies and the time needed to develop
vaccines, we propose strategies that focus on blunting the pathobiology
that we hypothesize results from ACEI/ACE2 imbalance and enhanced ANG II
signaling that occurs with SARS-CoV-2 infection.

\textbf{Figure 1. A schema identifying the tissues impacted by
SARS-CoV-2 infection and COVID-19 pathobiology} . Dashed arrows identify
events whose role is as-yet unclear\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2. Renin-Angiotensin signaling (RAS), Angiotensin (ANG
II) signaling, the balance between ACE1 and ACE2, and in red, the impact
of COVID-19.} APs: Aminopeptidases; PREP: prolyl endopeptidase; MME:
membrane metalloendopeptidase

\emph{The Renin-Angiotensin signaling (RAS) pathway}

\textbf{Figure 2} shows a schema of the RAS pathway and is based on data
for angiotensin signaling from a range of sources (Santos, 2014; Zhuo et
al., 2013; Tikellis and Thomas, 2012; Karnik et al., 2017, Santos et
al., 2019), including the Guide to Pharmacology database (GtoPdb;
https://www.guidetopharmacology.org/) (Armstrong et al., 2020). In the
``traditional''/canonical RAS pathway, renin is secreted from the kidney
and angiotensinogen (AGT) is produced and secreted by the liver. Renin
cleaves AGT to form Angiotensin 1 (ANG 1), which in turn generates ANG
II or ANG 1-9, primarily from the actions of ACE1 and ACE2,
respectively. ANG II is cleaved by multiple enzymes, most importantly
ACE2, to form ANG (1-7). ANG II also forms ANG IV via the action of
aminopeptidases (APs). Both ANG II and ANG IV act primarily via AGTR1 (a
GPCR). ANG (1-7) acts primarily via the MAS1 (a GPCR), and forms ANG
(1-5), which signals via MRGPRD (a GPCR). ANG (1-7) can also act via the
AGTR2 receptor but with much lower affinity than ANG II (refer GtoPdb
entry).

As discussed below, the lung and heart express components of the RAS
system, i.e., `local' RAS signaling (e.g., Uhal et al., 2012; Forrester
et al., 2018), that can contribute to tissue injury. For example,
activated lung fibroblasts and injured epithelial cells express AGT and
other RAS components (e.g., Uhal et al., 2012; Wang et al., 2000).

ACE2, a carboxypeptidase (zinc metalloprotease), is the primary enzyme
responsible for ANGII degradation, thus regulating signal transduction
by ANGII. The conversion by ACE2 of ANG II to ANG (1-7) (and its
signaling via MAS1) produces effects that oppose those of ANG II (Karnik
et al., 2017, Santos et al., 2018; Santos et al., 2019). ACE2, in
particular its catalytic ectodomain, can be shed from cells, an action
mediated by the metalloprotease ADAM17, into the circulation as soluble
ACE2, levels of which can be increased by Ang II via its ability to
increase ADAM17 activity (Lambert et al., 2005; Patel et al., 2014).

The RAS signaling pathway (\textbf{Figure 2)} thus relies on a
``yin/yang relationship'' between ACE1 and ACE2: ACE1 generates
Angiotensin II (ANG II) and in turn, signaling by the GPCRs AGTR1 and
AGTR2 while ACE2 generates peptides whose receptors act to oppose
responses mediated by AGTR1. AGTR1 is highly expressed and mediates
ANGII signaling and effects (including inflammation, apoptosis,
pro-fibrotic signaling and tissue remodeling) in pulmonary and cardiac
tissue (Forrester et al., 2018). By contrast, the role of AGTR2, which
is expressed in the lung and at low levels in the heart, is more
controversial (Forrester et al., 2018; Santos et al., 2019; GtoPdb).
AGTR2 can mediate effects that oppose those of AGTR1 but other data
suggest that AGTR2 promotes effects such as apoptosis. In subsequent
section that focus on the pathophysiology of COVID-19, we emphasize the
role of ACE1-generated AGTR1 as the key mediator of ANG II actions and
the opposing actions of ACE-derived peptides.

\emph{SARS viruses and Angiotensin signaling}

Infection of cells by SARS viruses that bind ACE2 results in two
effects: inhibition of ACE2 activity and decrease of ACE2 expression in
infected cells (Kuba et al., 2005; Haga et al., 2008; Glowacka et al.,
2010; Dijkman et al., 2012; Zhang et al., 2020). Indirect evidence for
the latter response in COVID-19 is data showing elevation in circulating
ANG II with viral infection and increased circulating ANG II peptide
with higher viral loads (Liu et al., 2020b).

Our hypothesis is founded on the following ideas that derive from data
in reports cited in ensuing sections:

\begin{enumerate}
\tightlist
\item
  SARS viruses decrease ACE2 activity and expression.
\item
  The decrease in ACE activity creates an imbalance in signaling by ACE1
  and ACE2 products
\item
  This imbalance increases ANG II/AGTR1 signaling and is superimposed on
  concurrent pathology (e.g., chronic lung disease, cardiac remodeling
  in the lung and heart, respectively). ANG II is a pivotal mediator of
  injury in both tissues; enhancement of its effects together with
  signaling from comorbidities can increase severity of COVID-19.
\item
  In patients more susceptible to the damaging effects of ANG II, the
  decrease in ACE2 activity by SARS viruses can unleash a cascade of
  injurious effects through a heightened imbalance in the actions of the
  products of ACE1 versus ACE2.
\item
  The proposed imbalance in the signaling and actions of products of
  ACE1/ACE2 implies the potential of pharmacological approaches that
  redress this imbalance via: a) decrease in ACE1 activity, b) blockade
  of AGTR1, and/or c) increase in ACE2-mediated signaling by
  affinity-trapping the SARs virus, enhancement of ACE2
  expression/activity, or d) by agonists for receptors of ACE2-derived
  peptides
\end{enumerate}

We provide data from the literature in support of this hypothesis, in
particular as related to the lungs and the heart, and regarding
potential therapeutic approaches that address the imbalance of ACE1/ACE2
signaling and resultant actions involved in the pathobiology and
severity of COVID-19.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3} . \textbf{Hypothesized model of cell-cell
communication and pathobiology in pulmonary infection from SARS-CoV-2
and the role of ACE1- and ACE2-derived peptides in mediating these
effects on several different cell types.}

\emph{A model for how imbalance in the RAS pathway produces COVID-19
injury in the lungs}

ACE2 is highly expressed in the lung parenchyma, particularly in type II
pneumocytes (type II alveolar cells) (Zou et al, 2020). Type II cells
synthesize and release pulmonary surfactant, phospholipids that lower
surface tension, which is necessary to maintain alveolar structure
(Andreeva et al., 2007). Type II cells also can differentiate to become
type I alveolar cells (which form the structure of alveoli), a mechanism
for replacement of type 1 cells that are damaged. The SARS-CoV-2 and
SARS-CoV-1 viruses perturb alveoli to produce the major pathology in the
lung, with increased fluid entry, cell death and inflammation along with
reduction in gas exchange and levels of surfactant (Hui et al., 2005;
Gralinksi \& Baric, 2015; Xu et al., 2020b).

\textbf{Figure 3} depicts a hypothetical framework for this process and
the cell types involved. The SARS-CoV-2 virus infects alveolar
pneumocytes by binding to ACE2, leading to a decrease in ANG II
conversion to ACE2-derived peptides, e.g. a reduction in ANG (1-7) and
its actions that counteract effects of ANG II (\textbf{Figure 2)} .
Hence, ANG II levels increase in the alveolar microenvironment, with
potential effects on multiple cell types. Below, we provide evidence in
support of this framework and the role of ACE1/ACE2 imbalance in the
lung injury of COVID-19.

ANG II has a pro-apoptotic action on pulmonary epithelial cells (Wang et
al., 1999a; Wang et al., 1999b; Wang et al., 1999c; Wang et al., 2000;
Papp et al., 2002), a response that is consistent with the pathology
from SARS viruses, i.e., widespread epithelial damage and alveolar
damage and cell death (Zhou et al., 2020a; Zhou et al., 2020b). In
addition, ANG II promotes and Ang (1-7) suppresses
epithelial-to-mesenchymal transformation (EMT), whereby epithelial cells
acquire a more fibrotic phenotype (Buckley et al., 2010; Rodrigues-D\selectlanguage{ngerman}íez
et al., 2008; Lee at al., 2013; Shao et al., 2019), a mechanism that may
contribute to the formation of pulmonary lesions. ANG II also decreases
the clearance of alveolar fluid (Deng et al., 2012a; Deng et al., 2012b;
Ismael-Badarneh et al., 2015). Apoptosis and EMT in alveolar epithelial
cells are accompanied by an increase in secretion of pro-inflammatory
cytokines (e.g., IL1-\selectlanguage{greek}β, \selectlanguage{english}IL-6, IL-8, MCP-1 and TNF-\selectlanguage{greek}α\selectlanguage{english}) (Aumiller et al.,
2013; Ma et al., 2010; Kode et al., 2006; Pires-Neto et al., 2013;
Pedersen \& Ho, 2020). Epithelial cells engage in crosstalk with immune
cells, in particular during infection and apoptosis (Rzepka et al.,
2012; Herold et al., 2012; Chuquimia et al., 2012). These effects are
compounded by the secretion of RAS components by activated
myofibroblasts and epithelial cells undergoing apoptosis (Wang et al.,
1999a; Wang et al., 1999b; Wang et al., 2000; Uhal et al., 2012),
thereby amplifying ANG II signaling in a positive-feedback loop.

ANG II also has pro-fibrotic effects on fibroblasts that reside in
interstitial spaces around alveoli (Marshall et al., 2000; Uhal et al.,
2007; Uhal et al., 2012b) and increases apoptosis of endothelial cells
and endothelial permeability in the surrounding capillary network
(Watanabe et al., 2005; Bodor et al., 2012), which can increase fluid
entry and immune infiltration into regions of the lung. ANG II also
affects various types of immune cells (Forrester et al., 2018),
increasing macrophage infiltration, ROS production and release of
pro-inflammatory cytokines. Besides immune cells, pathological ROS
production occurs in pulmonary fibroblasts, driven by ANG II stimulation
and inhibited by the actions of ACE2/ANG (1-7) (Meng et al., 2015). ROS
production from activated fibroblasts is a key driver of epithelial
injury in models of pulmonary fibrosis (Sakai \& Tager, 2013).

Crosstalk among epithelial cells, fibroblasts and immune cells suggests
a role for macrophages, which are activated by pulmonary epithelial
cells in injury settings and can create positive feedback that promotes
inflammation (Uhal et al., 2007; Rzepka et al., 2012; Herold et al.,
2012; Chuquimia et al., 2012; Bhattacharya \& Westphalen, 2016). Such
effects can occur in response to ANG II (Uhal et al., 2007). Ang II can
also regulate the function of other immune cells (e.g., dendritic cells
and neutrophils) that can promote lung injury (Grommes \& Soehnlein,
2011; Florez-Sampedro et al., 2018). Importantly, as summarized below,
ANG (1-7) has opposing effects that counteract this pathology; these
protective effects are blunted by the SARS-CoV-2 virus.

ANG II thus promotes a range of pro-apoptotic, inflammatory, fibrotic
and edema-associated processes in the alveolar microenvironment. As cell
death occurs, the epithelium, a critical component of innate immunity as
a barrier to pathogens and via its formation and release of surfactant
(Wright, 2003; Eisele and Anderson, 2011) becomes compromised, paving
the way for secondary infection (e.g., bacterial pneumonia). As a
result, immune response is further enhanced, greater inflammation ensues
(\textbf{Figure 3} ) and alveolar damage is increased, thereby enhancing
lung injury and edema. Patients who recover may have severe tissue
damage, potentially with tissue fibrosis. Indeed, studies in patients
who recovered from SARS-1 document the presence of fibrosis and chronic
lung damage in severe cases (Ketai et al., 2006). Lung tissue from
COVID-19 patients shows evidence of a) epithelial injury and disruption,
in particular of type-2 pneumocytes, b) invasion of macrophages and
neutrophils and c) initiation of fibrosis (Luo et al., 2020; Tian et
al., 2020; Dhama et al., 2020; He et al., 2020).

\emph{Benefits of ACEI/ARB use in reducing pulmonary injury}

Numerous studies have assessed the effects of inhibition of ANG II
signaling by the administration of ACEIs or ARBs as ways to mitigate
lung injury in a range of experimental models, including ARDS and
pulmonary fibrosis. Bleomycin, a natural product-derived peptide used
for cancer chemotherapy, is a widely used model in rodents for the study
of pulmonary fibrosis. Bleomycin damages the pulmonary epithelium, which
then initiates a fibrotic response; the pulmonary injury and fibrosis
can be mitigated by treatment with ACEIs or ARBs (e.g., Li et al., 2003;
Wang et al., 2000; Otsuka et al., 2004; Yao et al., 2006; Uhal et al.,
2012). Other models of lung fibrosis, e.g. \selectlanguage{greek}γ-\selectlanguage{english}irradiation, also show
deceased injury and fibrosis in response to ARBs (Mohammadi-Karakani et
al., 2006; Molteni et al., 2007; Uhal et al 2012). ACEIs/ARBs appear to
blunt the degree of apoptosis of epithelial and other cell types,
indicating that initiating events of lung injury require ANG II
signaling to drive a pathological response.

How might this occur? As shown in \textbf{Figures 2 and 3} , increase in
local RAS signaling within the lung, i.e., injury-induced production of
RAS signaling components by epithelial cells and activated fibroblasts,
promotes pulmonary injury and helps explain the efficacy of ACEIs/ARBs
in blunting this pathology. Further evidence for this mechanism is the
reduction in bleomycin-induced injury and fibrosis by antisense
oligonucleotides against AGT (Li et al., 2007).

Data from other in-vivo models supports the utility of ACEIs/ARBs in
blunting lung injury, especially of the epithelium, thus further
implicating the role of ANG II in mediating these effects. Examples
include acute lung injury induced by oleic acid in rats (in which use of
the ACEI captopril reduced alveolar damage/epithelial disruption,
endothelial damage and infiltration of neutrophils (He et al., 2007),
the protective effect of ACEI/ARB treatment in reducing pneumocyte death
in surfactant-depleted rat lungs (Lukkarinen et al., 2005), and the
efficacy of ACEIs in the treatment of radiation-induced lung injury
(Medhora et al., 2012). This benefit has also been shown in human
studies, for example, a reduction in pulmonary-related mortality by
captopril administered to patients receiving total body irradiation
prior to hematopoietic stem cell transplantation (Cohen et al., 2012).
ACEI administration also reduces radiation-induced pneumonitis in lung
cancer patients (Kharofa et al., 2012).

Further evidence for effects of sepsis has been obtained from animal
models of acute lung injury (ALI) induced by lipopolysaccharide (LPS):
treatment with the ARB losartan reduced pro-inflammatory cytokine
secretion and lung injury and improved survival, while also reducing ANG
II production in the lungs (Shen et al., 2009). The protective effects
of losartan in LPS-induced ALI are associated with reduced contribution
by dendritic cells to inflammation (Liu et al., 2012). Captopril was
protective in a rat LPS-induced ALI model, reducing immune cell
infiltration, edema, and hemorrhage in alveoli (Li et al, 2015). The
latter study also showed that the ratio of ACE1/ACE2 expression
increased in injury and that captopril attenuated injury and decreased
that ratio. These findings were replicated in a study in which captopril
reduced inflammatory cytokines and monocyte infiltration in
bronchoalveolar fluid (Boskabadi et al., 2019). In addition, in a murine
H5N1 influenza infection model. treatment with losartan improved
survival and reduced edema, lung injury and immune cell infiltration
(Yan et al., 2015). Other studies showed that ACEIs or ARBs inhibit
ventilator-induced lung injury (Jiang et al., 2007, W\selectlanguage{ngerman}östen-van Asperen
et al., 2008, Jerng et al., 2007, Chen et al, 2014). Also, treatment of
rats with losartan in chronic cigarette-smoke-induced injury model
reduced pulmonary remodeling and pulmonary arterial hypertension (Han et
al., 2010).

Data from retrospective studies in humans show that ACEIs can prevent or
reduce the severity of pneumonia (e.g., Mortensen et al., 2005; van de
Garde et al., 2007; Mortensen et al., 2012 and Caldeira et al., 2012).
In addition, reatment with ACEIs/ARBs in COPD (chronic obstructive
pulmonary disease) reduces inflammation, comorbidities and disease
complications (Shrikrishna et al., 2012). Retrospective analyses also
suggest that ACEI/ARB treatment may reduce mortality in ARDS/ALI
(Noveanu et al., 2010) and mitigate the effects of radiation pneumonitis
(Harder et al., 2015). However, evidence is lacking from prospective
clinical studies with ACEIs/ARBs in these types of pulmonary injury.

Cell-based assays provide additional support for the importance of ANG
II in mediating lung injury. ANG II induces apoptosis in a human
epithelial cell line (A459) and in rat type-II pneumocytes, effects that
are blocked by treatment with ACEIs or ARBs (Wang et al., 1999b, Wang et
al., 1999c). Such findings were replicated using losartan in the same
cell types, results that confirmed AGTR1 as the receptor that promotes
apoptosis in pulmonary epithelial cells (Papp et al, 2002). Moreover,
treatment of human and rat lung epithelial cells with FAS protein (an
apoptosis-inducing ligand) induced apoptosis by increasing AGT and ANG
II expression/secretion, effects blocked by ANG II antibodies (Wang et
al., 1999b). The latter authors further showed that pro-fibrotic human
lung fibroblasts induce epithelial cell apoptosis by producing ANG II
and that these myofibroblasts express the components necessary to drive
a local RAS signaling cascade (Wang et al., 1999a; Wang et al., 1999c).
In addition, the ARB telmisartan blunts ANG II-promoted EMT of A549
cells (Buckley et al., 2010).

Thus, the available data provide consistent evidence indicating that ANG
II signaling, via AGTR1, has a central role in lung injury. Blunting
this signaling by ACEIs or ARBs has beneficial effects in modulating
such damage, including in the context of acute pulmonary injury caused
by infection.

\emph{ACE2 and ANG (1-7) reduce pulmonary injury}

An extensive literature has emerged describing the protective effects of
ACE2 and ANG (1-7) in mitigating pulmonary injury by acting in
opposition to the effects of ANG II. The approaches include treatment
with soluble ACE2 that ultimately converts ANG II to ANG (1-7), whose
protective role is most likely mediated by MAS1.

Data from rodent models indicate that ACE2/ANG (1-7) can mitigate
fibrosis induced by agents such as bleomycin. For example, in a mouse
bleomycin model, treatment with recombinant ACE2 reduced epithelial
injury, pro-fibrotic cytokine release, activation of fibroblasts and
inflammatory cell infiltration, thereby prominently reducing the extent
of lung injury (Wang et al., 2015). Studies in a bleomycin model in rats
have revealed that the protective effects by ANG (1-7) may occur by
inhibition of signaling cascades that involve MAP Kinase and NFkB (Meng
et al., 2014). The authors also found the ANG (1-7) or ACE2
overexpression had antifibrotic effects via inhibition of MAP Kinase and
NFkB in human lung fibroblasts. Other studies confirm a protective role
by ACE2/ANG (1-7) in bleomycin-treated rats (Wu et al., 2014). Lung
samples from patients with idiopathic pulmonary fibrosis (IPF) or from
bleomycin-treated mice and rats have decreased ACE2 expression in
association with lung injury and fibrosis (Li et al., 2007). Fibrosis
(collagen accumulation) was also enhanced in mice treated with ACE2
siRNA or ACE2 inhibition but treatment with recombinant ACE2 reduced
bleomycin-induced fibrosis (Li et al., 2008b). In a cigarette
smoke-induced model of lung injury in mice, Zhang et al., (2018) showed
that treatment with ANG 1-7 reduced lung inflammation and fibrosis.

ACE2/ANG (1-7) also have a protective effect in ALI/ARDS models induced
by LPS stimulation. In LPS-induced ARDS models in rats, treatment with
ANG (1-7) or an ARB reduced lung injury and inflammation and improved
lung function (Wösten\selectlanguage{english}-van Asperen et al., 2011; (Chen et al., (2013). He
et al., (2015) reported that mesenchymal stem cells (MSCs) engineered to
overexpress ACE2 had strong protective effects in an ALI model,
improving endothelial barrier integrity and reducing lung injury and
inflammation. Inhibition of ACE2 increased lung injury, IL-17 signaling
and inflammation with infiltration by neutrophils in a murine model of
bacterial (Pseudomonas) lung infection but the converse occurred in mice
treated with recombinant ACE2 (Sodhi et al., 2019). ACE2 not only
mitigated lung injury but also improved response to the infection.
Ex-vivo experiments with mouse lung organoids confirmed the effects of
ACE2 limiting IL-17 signaling.

In-vitro data with human cells support the idea that ACE2/ANG (1-7) can
protect cells from ANG II or bleomycin-induced apoptosis. It has been
suggested that endoplasmic-reticulum (ER) stress induces apoptosis,
which can be eliminated by treatment with ANG (1-7) via MAS1 receptor
activation (Uhal et al., 2011; Uhal et al., 2013). TGF-\selectlanguage{greek}β\selectlanguage{english}1 treatment
promotes EMT in human airway epithelial cells, a response associated
with a reduction of ACE2 expression and elevation of migration and
expression of myofibroblast markers; treatment with ANG (1-7) blocked
TGF-\selectlanguage{greek}β\selectlanguage{english}1-induced EMT and activation of targets downstream of TGF-\selectlanguage{greek}β\selectlanguage{english}1 (Shao
et al., 2019).

Effects of the MAS1 receptor in modulating immune response have been
reported in a number of studies. These include effects of MAS1 on
neutrophil influx in models of arthritis in mice and rats (Silveira et
al., 2010) and on the ability of macrophages to phagocytose neutrophils
that have undergone apoptosis (Barroso et al., 2017). MAS1 knockout mice
have greater inflammatory cell infiltration, lung remodeling and
inflammatory cytokine production in models of allergic pulmonary
inflammation (Magalh\selectlanguage{ngerman}ães et al., 2016) and altered macrophage function
that contributes to a range of inflammatory pathology (Hammer et al.,
2016).

Thus, considerable data document a protective role for ACE2/ANG (1-7) by
opposing effects of ANG II in lung injury. ACE2/ANG (1-7) have many such
actions, which include blunting of alveolar epithelial apoptosis,
infiltration of inflammatory cells, activation of fibroblasts and
endothelial disruption.

\emph{ACE2 in SARS-CoV infections of the lung}

In a landmark study, using mouse models of acid-respiration or LPS, the
Penninger group initially showed a protective role of ACE2 in ARDS (Imai
et al., 2005) and demonstrated that ACE1-mediated signaling promotes
ARDS but ACE2 exerts strong protective effects. ACE2 knockout (KO) mice
had dramatically increased lung injury, effects that were reduced by
treating with recombinant human ACE2. Conversely, ACE-deficient mice had
reduced severity of injury, supporting the concept that ACE1/ACE2
balance is a central mediator of lung injury.

The Penninger group subsequently used ACE2 KO mice and found that ACE2
expression is necessary for SARS infection (Kuba et al., 2005). The
authors hypothesized that RAS signaling blockade or treatment with
recombinant ACE2 would protect from SARS-induced injury. A crucial
observation was that SARS-CoV-infected mice resembled ACE2 KO mice in
their susceptibility to lung injury (Kuba et al., 2006). Penninger and
coworkers have extended these ideas to COVID-19, advocating for the use
of ACE2 as a target in SARS-CoV-2, including by providing soluble ACE2
(Zhang et al., 2020). The Penninger group recently showed the efficacy
of recombinant human ACE2 in drastically reducing the infectivity of
SARS-CoV-2 in ex-vivo models, including with organoids (Monteil et al.,
2020).

\emph{What is the contribution of AGTR2 to pathobiology in the lung and
COVID-19?}

Few studies have assessed the actions of AGTR2 in the lung. A protective
role for AGTR2 in was implied by findings indicating that AGTR2-null
mice and those treated with an AGTR2 inhibitor were more vulnerable to
ARDS Imai et al., (2005). However, subsequent studies related to the
lungs using selective inhibitors of AGTR2 to distinguish its effects
from AGTR1, reach the opposite conclusion: in general, it appears AGTR2
drives pathology synergistically with AGTR1, in particular in cell types
relevant to the hypothesis presented above.

Examples of such studies include animal models of fibrosis (Königshoff
et al., 2006; Waseda et al., 2008) and \emph{in-vitro} data from human
lung fibroblasts (Königshoff et al., 2006). AGTR2 also promotes
apoptosis in pulmonary endothelial cells (Lee et al., 2010), rat
alevolar epithelial cells (Bechara et al., 2006) and human alveolar
epithelial cell lines (Pickel et al., 2010). Consistent with animal data
on fibrosis are histological data from patients with systemic sclerosis
and lung fibrosis, showing elevated alveolar AGTR2 expression with
disease; higher AGTR2 expression is associated with increased mortality
Parra et al., (2014).

Reviews that discuss AGTR2 action in other tissues (e.g., Forrester et
al., 2018; Lemarie \& Schiffrin, 2010; Jones et al., 2008; Kaschina, \&
Unger, 2003) also note disagreement regarding AGTR2 action (e.g.,
effects on vasodilation, protection from ischemic injury), but all
concur that AGTR2 exerts pro-apoptotic effects in various cell types. A
pro-fibrotic role for AGTR2 that promotes injury in concert with AGTR1
has also been noted in lung fibroblasts Uhal et al., (2012b). We
conclude that AGTR2 may act in parallel with AGTR1 in driving cell death
and tissue damage in the schema depicted in \textbf{Figure 3} .

\emph{}

\emph{How is the pathobiology of lung injury related to ACE1/ACE2
imbalance counteracted?}

The data described above leads us to propose a model for pulmonary
pathology based on imbalance in RAS signaling that influences multiple
cell types (\textbf{Figure 4} ) and has feedback loops that amplify
pathobiology. Most COVID-19 patients suffer minor illness and avoid
severe tissue injury. We propose that this occurs via an effective
adaptive immune response that eliminates infection and prevents the
damage induced by the RAS pathway and associated feedback mechanisms. By
contrast, patients with underlying pathologies suffer more severe
disease because of amplified RAS-driven mechanisms. These mechanisms
cause acute injury that exceed the capacity of the protective immune
response. The damaging effects of the virus via RAS/Ang II are thus
competing with the effectiveness of the immune response (\textbf{Figure
4} ).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 4. ACE1/ACE2 imbalance, lung injury, and factors that
determine severe pathology or mild illness. (A.)} A model for the course
of COVID-19 that links ACE1/ACE2 imbalance to lung injury via the RAS
pathway and the protective role of the immune response. \textbf{(B.)} An
illustration of the predicted course of COVID-19 in two settings:
\textbf{top} : Severe pathology, in patients who lack appropriate immune
response or who have prior conditions that enhance ACE1/ACE imbalance
(and RAS-induced injury). The result is increased injury that overwhelms
the adaptive immune response; \textbf{bottom} : Mild illness, in which
patients lack underlying conditions and can mount an appropriate immune
response, so that RAS-induced injury is less serious, an effective
immune response occurs and the infection is resolved.

Early insights into the immune response to COVID-19 have been reported
(To et al., 2020, Thevarajan et al., 2020 and Zhou et al., 2020) along
with the proposed models of this response (Li et al., 2020; Prompetchara
et al., 2020). Analysis of the immunopathology of SARS-1 and MERS
(Channappanavar and Perlman, 2017) is consistent with such data and
models. Prior reviews describe the importance of T cell-mediated
adaptive immune response to coronaviruses, especially SARS
(Channappanavar et al. 2014) and Li et al., 2009) and provided insight
into roles of macrophages, dendritic cells, B cells and T cells in
SARS-CoV-1 infection (Zhao et al., 2009; Yasui et al., 2014).

Based on these studies, the following framework describes the interplay
between pathological---as opposed to protective-- immune response and
acute pulmonary injury in COVID-19, in part extrapolating from
information and ideas related to SARS-CoV-1 (Channappanavar and Perlman
2017).

\begin{enumerate}
\tightlist
\item
  During early stages of infection, inflammatory cells (macrophages,
  neutrophils and dendritic cells) infiltrate into the alveoli in
  response to cytokine secretion by alveolar cells. Immune infiltration
  is greater in subjects who experience more rapid RAS-induced injury
  and epithelial cell death (i.e., a more severe imbalance between ACE1
  and ACE2), thereby establishing a positive feedback loop: accumulation
  of large numbers of inflammatory cells further promotes cell death in
  alveoli.
\item
  Human coronaviruses express proteins that suppress the production by
  immune cells of interferons (IFNs), which suppress viral replication.
  This IFN response is exacerbated and injury is increased in conditions
  of `hyper-inflammation' that undermine protective innate immune
  responses. Such hyper-inflammation is more likely to occur in
  conditions of escalated RAS-driven injury, due to greater ACE1/ACE2
  imbalance.
\item
  Seroconversion begins early, within \textasciitilde{}5 days from the
  onset of symptoms, with increasing titers of IgM antibodies, and
  promotes an adaptive immune response, mediated by T helper cells,
  cytotoxic T cells and antibody production by B cells, recruited by T
  helper cells. Hyper-inflammation results from extensive injury that
  overwhelms this adaptive response, with accumulation of activated
  macrophages that can suppress effective antigen presentation by
  dendritic cells and the recruitment of T cells.
\item
  In patients with mild pulmonary injury, effective recruitment of T
  cells leads to clearance of the virus, followed by tissue repair and
  restoration of homeostasis. Transition occurs from IgM to IgG
  antibodies. In the case of severe pathology, a vicious cycle of
  inflammation and cell death leads to widespread epithelial disruption
  and onset of pneumonia. Such patients are more vulnerable to bacterial
  infection with the decrease in surfactant production and loss of an
  intact epithelial barrier.
\item
  Mild disease (with less severe RAS-driven effects) shows a progressive
  decline in viral loads and improvement in symptoms and signs of
  infection, generally by \textasciitilde{}7 days from initial symptoms.
  In progressive disease (with more severe RAS-driven effects), greater
  pulmonary injury (perhaps with secondary pneumonia) necessitates
  critical care, including assisted ventilation. ARDS can develop if
  inflammation, cell death and infection continue. Cardiac complications
  may exacerbate this, especially if myocarditis and further pulmonary
  edema occur. The cytokine storm stemming from ARDS also has the
  potential to exert systemic effects, raising the risk of multiple
  organ failure (Pedersen \& Ho, 2020).
\end{enumerate}

The outcome of COVID-19 infection is thus determined by the competing
actions of different elements that promote (the RAS pathway) or blunt
(immune response) lung injury (\textbf{Figure 4} ). In severe cases, a
series of injurious effects unfold and overwhelm protective immune
responses. Greater imbalance in the effects if ACE1 and ACE2 in the RAS
pathway is predicted to exacerbate pathology, making it more likely that
the immune response will be overcome. Factors/comorbidities that
increase the ACE1/ACE2 imbalance are discussed below.

\emph{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\emph{A model for how imbalance in the RAS pathway produces COVID-19
injury in the heart} \textbf{}

\textbf{Figure 5} . \textbf{Hypothesized model of cell-cell
communication in myocardial infection from SARS-CoV-2 and the influence
of ACE1/ACE2 imbalance on a variety of cell types involved in cardiac
injury.}

By analogy with our model for lung injury from COVID-19 (\textbf{Figure
3} ) and based on data in the literature, \textbf{Figure 5} describes a
model for COVID-19 pathology in the heart. Below, we discuss details of
this model.

ACE2 is highly expressed in the myocardium in particular on cardiac
myocytes but also in endothelial cells and fibroblasts (Patel et al.,
2016; Santos et al., 2018). The binding of SARS-COV-2 to ACE2 from
Infection of the myocardium decreases ACE2 activity (Oudit et al., 2009)
and results in increased ACE1/ANG II driven signaling and a decrease in
effects of ACE2-derived peptides, including ANG (1-7). ANG II alters the
function of multiple cell types in the heart, including cardiomyocytes,
fibroblasts, endothelial cells and inflammatory cells, in particular
macrophages. ANG (1-7) action occurs on cardiomyocytes, inflammatory
cells and cardiac fibroblasts.

Akin to the lung, the heart has a local RAS that can contribute to
cardiac pathology (Dostal and Baker, 1999; De Mello and Danser, 2000;
Reyes et al., 2017; Forrester et al., 2018). ANG II has direct effects
on cardiomyocytes, increasing hypertrophy and contractility, altering
heart rate and rhythm, and enhancing secretion of cytokines that help
facilitate cardiac remodeling (Baker et al., 1992; Wen et al., 2012;
Reyes et al., 2017; Forrester et al., 2017). ANG II converts cardiac
fibroblasts to a more pro-fibrotic myofibroblast phenotype and enhances
secretion of factors (in particular TGF-\selectlanguage{greek}β \selectlanguage{english}and RAS signaling components)
that promote hypertrophy via crosstalk with cardiomyocytes (Dostal and
Baker, 1999; Singh et al., 2008; Frieler and Mortensen, 2016; Forrester
et al., 2018). ANG II also exerts effects on endothelial cells, inducing
endothelial dysfunction and cytokine secretion, in particular of
endothelin-1, which enhances myocyte hypertrophy (Schmermund et al.,
1999; Forrester et al., 2018). RAS signaling can promote
pro-inflammatory effects on inflammatory cells, in particular cardiac
macrophages, which can further increase myocyte hypertrophy and
fibroblast activation (Frieler and Mortensen, 2016; Forrester et al.,
2018). ANG II signaling in multiple cardiac cell types increases
oxidative stress and reactive oxygen species (ROS) (Wen et al., 2012;
Kurdi and Booz, 2012; Forrester et al., 2018).

Signaling in the heart by ACE2-derived peptides, in particular ANG
(1-7), opposes effects of ANG II (Patel et al., 2016; Santos et al.,
2018). Via those actions, the ACE2- ANG (1-7)-MAS1 axis mitigates
hypertrophic, fibrotic, oxidative stress and remodeling effects of ANG
II. Protective effects via ACE2 on cardiac myocytes are likely
particularly important in cardiomyopathy and heart failure (e.g.,
Flores-Mu\selectlanguage{ngerman}ñoz et al., 2011).

ANG II thus alters multiple cell types in the heart and promotes a
pro-inflammatory, hypertrophic state via a range of mechanisms. These
mechanisms are counteracted by ACE2-derived products, in particular ANG
(1-7), implying an alteration in ACE1/ACE2 balance as a contributor to
the resultant cardiac phenotype. The SARS-CoV-2-promoted increase in
ACE1/ANG II actions resulting from a decrease in ACE2-derived peptides
is predicted to unleash inflammatory, oxidative stress and remodeling
events and potentially myocyte apoptosis, depressed myocardial function,
heart failure, arrythmia, and cardiac fibrosis.

\emph{Enhanced ACE1/ACE2 imbalance in comorbidities that influence
COVID-19 morbidity and mortality}

Why do some patients, with comorbidities have increased susceptibility
to morbidity and mortality from COVID-19? Our model for pulmonary and
cardiac injury implies a role for crosstalk between ACE2-expressing
cells infected by SARS viruses and other cell types, especially
inflammatory cells (e.g., macrophages and neutrophils) and fibroblasts.
In patients with underlying disease, one or more of these cell types may
be dysfunctional. Superimposed SARS-CoV-2 infection further amplifies
ANG II signaling (which promotes injury) and suppresses ANG (1-7)
signaling (which opposes injurious effects), thus increasing
pathobiology. Multiple clinical conditions may be associated with
elevated vulnerability to COVID-19. Examples include:

\emph{Chronic Lung Injury/Disease} . Lung injury (e.g., from fibrotic
disease, smoking or radiation) is associated with increased local
inflammatory signaling, predisposing the epithelium to ANG II-promoted
injury. In these settings, epithelial cells and fibroblasts can have
elevated a net increase in pro-inflammatory ANG-mediated responses. The
addition of SARS-CoV-2 further increases this imbalance, thereby
enhancing lung injury.

\begin{itemize}
\tightlist
\item
  \emph{Cardiac hypertrophy and remodeling} . ANG II regulates cardiac
  remodeling in multiple settings, including hypertension. The elevation
  in ANG II signaling, derived in part from cardiac RAS, increases
  effects of ANG II in the heart (Forrester et al., 2018). Patients with
  cardiac pathologies associated with remodeling are thus particularly
  susceptible to an acute imbalance in the RAS pathway caused by
  myocardial SARS-CoV-2 infection. Decreased cardiac function,
  especially in patients with left heart failure, may also increase the
  likelihood of pulmonary edema, accompanying pulmonary infection and
  complications.
\item
  \emph{Diabetes, obesity, metabolic syndrome and chronic inflammatory
  disease} . Advances in the understanding of the immune system and
  chronic inflammation have led to the concept of `inflammageing',
  whereby aging is associated with the advent of chronic inflammation,
  and the presence of inflammation-associated illnesses, including
  Type-2 diabetes (Ferruci and Fabbri, 2018; Fulop et al., 2018;
  Castelo-Branco, 2013). Chronic inflammation is also predicted to rise
  with obesity (Ferruci and Fabbri, 2018), a risk factor for COVID-19
  morbidity. Inflammation is a key mechanism by which elevated ANG II
  signaling and ACE1/ACE2 imbalance causes injury (\textbf{Figures 3-5}
  ). Certain patients with Type 2 diabetes and obesity also have
  hypertension and hypercholesterolemia; together, these features
  characterize the metabolic syndrome. The metabolic syndrome is
  associated with chronic inflammation, which may be a causative feature
  of this syndrome (Monteiro \& Azevedo, 2010; Donath et al., 2019).
  Increased RAS activity appears to be a pathogenic factor in metabolic
  syndrome (Skov et al., 2014). Patients with the metabolic syndrome are
  `pre-sensitized' to RAS-mediated effects and hence, more vulnerable to
  dysregulation of RAS by COVID-19.
\item
  \emph{Weakened adaptive immune response} . Within the inflammageing
  paradigm, aging-associated chronic inflammation via the innate immune
  system is coupled with a weakened adaptive immune response. The
  adaptive immune system thus has a reduced ability to establish a
  defense against SARS-CoV-2, allowing greater viral infectivity and
  opportunities for tissue injury. Immune-compromised subjects from
  other causes (e.g. those on immune-suppressive medications) would also
  be more vulnerable to SARS-CoV-2/COVID-19.
\item
  \emph{ACE polymorphisms} . ACE1 insertion/deletion polymorphisms (I/D)
  have been widely studied. The D-allele is associated with higher ACE1
  activity. Patients with the D allele, especially those with the D/D
  genotype, are at higher risk of morbidity and mortality from ARDS
  (Adamzik et al., 2007) and certain cardiac, pulmonary and inflammatory
  conditions (Gard, 2010; Zhou et al., 2010). The ACE1/ACE2 imbalance
  hypothesis predicts that patients with the D allele of ACE1, in
  particular the D/D genotype, will have elevated severity of COVID-19,
  as was seen in patients with SARS-1 (Itoyama et al., 2004).
\end{itemize}

Therefore, the ACE1/ACE imbalance model for SARS-CoV-2 pathobiology can
help explain how/why patients with certain underlying
conditions/comorbidities are at greater risk if infected with
SARS-CoV-2/COVID-19. Elderly individuals are at particular risk, since
many of the comorbidities are age-associated. Those with health
conditions such as immune deficiencies, diabetes, or cardiac disease
will likely be at greater risk for more severe COVID-19 infections and
ACE1/ANGII-mediated pathology. By contrast, children (who lack
comorbidities associated with ACE1/ACE2 imbalance) are predicted to have
less morbidity and mortality from COVID-19.

\emph{}

\emph{Opportunities to target the Angiotensin pathway}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

\textbf{Figure 6.} \textbf{Pharmacological agents that target the RAS
pathway and counteract effects of SARS-CoV-2 infection.}

The concepts and data discussed above suggest a variety of approaches
that may decrease the pathobiology of SARS-CoV2 infection resulting from
the imbalance in signaling by peptides generated by ACE1 and ACE2
(\textbf{Figure 6} ). Several complementary strategies might improve the
clinical status and outcome of patients with COVID-19. The goal of these
approaches is to restore ACE1/ACE2 balance in favor of ACE2-derived
peptides. The proposed therapies, discussed below, are directed at: 1)
Inhibition of ACE1; 2) Inhibition of the binding of SARS-Cov-2 to ACE2;
3) Agonism of receptors activated by ACE2-derived peptides; and 4)
Inhibition of AGTR1 (ARBs) (\textbf{Table 1} ).

\emph{Inhibition of ACE1}

The ability of ACE1 to generate ANG II is a critical step in providing
the ``driver'' for multiple features of the pathophysiology of COVID-19.
ACE1 (also known as dipeptidyl carboxypeptidase 1) is a zinc
metalloenzyme that removes a dipeptide from the C-terminus of certain
peptides, including His-Leu from the inactive decapeptide ANG I to
generate ANG II, the active octapeptide. ACE inhibitors approved for
clinical use are competitive peptide antagonists that blunt ANG II
formation but also the cleavage by ACE1 of the peptide bradykinin. We
have found no studies that assessed the efficacy of ACE1 inhibitors in
SARS-1 infections. The decrease in ANG II formation would likely be
beneficial in such infections. However, since a substantial proportion
(\textasciitilde{}20\%) of patients administered ACEIs develop cough as
a side effect (generally attributed to an increase in bradykinin) and
dry cough is a feature of COVID-19 infection, this is a potential
drawback to this approach.

\emph{Inhibition of the binding of SARS-Cov-2 to ACE2}

As ACE2 is the key cellular receptor for SARS-Cov-2, approaches that
block its interaction with the virus have the potential to maintain ACE2
activity and its generation of products, such as ANG (1-7) that
counteract pathological actions of ANG II. One such approach is to use
soluble ACE2 as a decoy to bind the virus and spare cellular ACE2 (Zhang
et al., 2020). A recombinant human ACE2, GSK2586881, has been tested and
was well-tolerated in Phase 1 studies and a Phase 2 trial with ARDS
patients (Khan et al., 2017). GSK2586881 was shown to reduce circulating
levels of ANG II and Interleukin-6 (IL-6). However, this study was not
powered to verify effects on clinical endpoints and direct therapeutic
effects on the lungs were unclear. A clinical trial investigating use of
recombinant human ACE2 in COVID-19 was initiated in China, but
enrollment was subsequently withdrawn (Clinical Trials.gov identifier
NCT04287686). Linkage of the extracellular domain of the ACE2 protein to
human immunoglobulin G Fc domain is a strategy that could have
advantages for treatment of COVID-19, including prolongation of the
half-life of ACE2 (Kruse, 2020; Liu P et al, 2018). A related ``decoy
approach'' is the use of the receptor binding domain (RBD) of the SARS S
protein that interacts with ACE2 (Wong et al., 2004; Han et al., 2006);
this approach has not yet been tested in patients. Small molecules have
been identified as inhibitors of coronavirus binding to ACE2 (Adedeji et
al., 2013) but their efficacy has only been evaluated in limited
pre-clinical studies (Adedeji \& Sarafianos, 2014). All these
approaches, which block viral entry into cells, maintain ACE2 activity
and thus would be expected to blunt disease pathobiology. By contrast,
agents that block later steps in viral infectivity (e.g., cellular
entry, endosomal inhibition, etc.) will likely yield decrease in ACE2
activity, which may be counterproductive with respect to the generation
of beneficial ACE2-derived peptides.

\emph{Agonism of receptors activated by ACE2-derived peptides}

Ang (1-7) is considered the major ACE2-derived peptide but ACE2 can also
generate other peptides, including Ang (1-9) and the heptapeptide
alamandine. Ang (1-7) primarily acts via the Mas-1 receptor
(\textbf{Figure 2} ) while response to Ang (1-9) may also involve AT2R;
alamandine has effects similar to Ang (1-7) via interactions with the
Mas-related GPCR, member D (MrgD) (Alexander at al., 2019).~ The actions
of the ACE2-Ang (1-7)-Mas-1 receptor, ACE2-Ang (1-9)-AGTR2 and
ACE2-alamandine-MrgD pathways generally oppose those of the Ang II-AGRT1
pathway, though this remains controversial for AGTR2, as discussed
earlier in this text. Activation of the former pathways, in particular
via GPCRs that mediate their effects, is thus predicted to blunt
COVID-19 pathobiology. Signaling by ANG (1-7) via Mas-1 can increase
activity of MAP kinase, phosphoinositide 3-kinase/Akt and NADPH oxidase
and subsequently activate effectors that include forkhead box protein 01
(FOXO1), cyclcooxygenase 2 (COX2) and generation of prostanoids and
nitric oxide (NO) (Santos et al., 2019; Povlsen et al., 2020). Less is
currently known regarding alamandine signaling and action. Additional
peptides may be generated as part of non-canonical (``non-classic'') Ang
II signaling (Santos et al, 2019), Efforts are underway to discover and
develop drugs that mimic the physiological peptides in their actions on
Mas-1 and Mrgd receptors. Initial clinical studies have tested an oral
formulation of hydroxypropyl-\selectlanguage{greek}β-\selectlanguage{english}cyclodextrin-ANG-(1-7) on muscle injury
(Becker et al., 2018). As recently reviewed (Wang et al., 2019),
targeting of non-canonical Ang signaling pathways has also been
initiated in studies of ARDS. Such approaches should be highly suitable
for testing in patients with COVID-19.

\emph{Inhibition of AGTR1 (ARBs) and potentially post-AGTR1 signaling
mechanisms}

Antagonism of AGTR1, the primary mediator of Ang II-promoted tissue
injury in SARS infections, is an attractive means to improve the
course/outcome of patients with COVID-19 by preventing and/or decreasing
such injury. This prediction is supported by data from studies of
ventilator-induced lung injury and ARDS (Wang D et al., 2019) and other
settings of tissue injury (e.g., Arumugam et al., 2016). A recent
preprint reported less morbidity and mortality in elderly COVID-19
patients with hypertension treated with ARBs prior to hospitalization
(Liu Y et al, 2020). Since numerous ARBs are approved drugs for other
indications (e.g., hypertension, heart failure, renal disease), such
ARBS could be rapidly tested as therapeutics on a compassionate use
basis and in trials to assess their efficacy for COVID-19. Although the
use of ARBs is potentially effective in decreasing lung and cardiac
injury from COVID-19, possible side effects, including systemic
hypotension, may occur in patients receiving those drugs.

\textbf{Table 1} summarizes information (including the pros and cons) of
each of those types of therapeutic approaches. Systemic administration
of drugs will likely be the focus of therapies for COVID-19 but should
administration by inhalation be considered for direct delivery to the
lungs (albeit collapsed alveoli in COVID-19 patients might limit such
delivery)? An important advantage of such an approach is to reduce
effects/complications from systemic administration. Clinical studies
have shown that inhaled NO or prostacyclin can improve oxygenation in
ARDS, but without improvement in mortality (Attaway et al., 2017). We
speculate that other inhaled agents might offer benefit in the lungs by
increasing cellular cAMP (e.g., agonists of \selectlanguage{greek}β-\selectlanguage{english}adrenoceptors or other
Gs-linked GPCRs), cGMP (e.g., guanylyl cyclase activators) or both
cyclic nucleotides (phosphodiesterase inhibitors). Given the importance
of inflammation to COVID-19 pathobiology, as discussed above and in
Pedersen \& Ho, (2020), inhalational administration of other
immunomodulatory/anti-inflammatory drugs may also have utility. Multiple
ACEIs and ARBs are available in solution and thus are potential
candidates for use with nebulizers. Such an approach might minimize
complications from systemic administration of those agents, of
particular importance in hypotensive patients or those at risk for
hypotension. Of note, both ACEIs and ARBs have been administered
experimentally via inhalational methods (Godugu et al., 2013; Suk et
al., 2019; Kim et al., 2020).

Much recent debate has occurred regarding the use of ACEIs and ARBs in
COVID-19 patients (Gurwitz, 2020; Danser et al., 2020; Diaz, 2020; Fang
et al., 2020; Bozkurt et al., 2020; Phadke and Saunik, 2020; Lewis,
2020; Patel and Verma, 2020; Vaduganathan M et al., 2020). Some authors
emphasize potential harms of these medications (e.g. Fang et al., 2020,
Diaz, 2020) whilst others argue against this idea (e.g. Danser et al.,
2020; Bozkurt et al., 2020) or hypothesize benefits of these drugs (e.g.
Gurwitz 2020; Phadke and Saunik, 2020; Patel and Verma, 2020). Most of
these articles are brief correspondences with limited supporting
evidence. As a result, health providers and patients have been confused
regarding the administration of ACEIs and ARBs to patients with
COVID-19.

Articles with concern regarding the potential harms of ACEI/ARB use in
COVID-19 generally cite articles that report administration of ACEI/ARBs
may increase ACE2 expression, thereby possibly increasing the risk and
spread of infection. We recently analyzed results from animal and human
studies and concluded that no consistent, replicable data provide
evidence of a relationship between ACEI/ARB use and ACE2 expression
(Sriram and Insel, 2020), Here, we focus on the potential benefits of
ACEI/ARB and other ways to target the RAS pathway in COVID-19, an idea
that others share, e.g., Zhang et al., (2020), who suggested ACE2 as a
target.

As listed below several clinical trials for COVID-19 have been initiated
that target the RAS pathway. These studies are mostly of small size and
are yet to begin enrollment. The targeting of the RAS for therapeutic
benefit has thus as-yet not received the attention given to other
approaches.

\begin{itemize}
\tightlist
\item
  NCT04335123: Study of Open Label Losartan in COVID-19. Phase-1 trial
  to evaluate losartan safety in COVID-19; University of Kansas Medical
  Center
\item
  NCT04312009: Losartan for Patients With COVID-19 Requiring
  Hospitalization; University of Minnesota
\item
  NCT04335136: Recombinant Human Angiotensin-converting Enzyme 2
  (rhACE2) as a Treatment for Patients With COVID-19
  {[}APN01-COVID-19{]}; Apeiron Biologics and multiple academic
  collaborators in Europe
\item
  NCT04332666: Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial
  (ATCO); Erasme University Hospital in Belgium
\end{itemize}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Therapeutic approach}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Pros}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Cons}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Comments}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ACE Inhibitors} \textbf{(ACEIs)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mitigates effects of ANG II in relevant cell types/tissues involved in
COVID-19 pathobiology Well-established clinical utility Well defined PK
and PD Large amount of preclinical animal data Oral administration.
Possible inhalable administration Generic Drugs, with established
production, supply chain and handling\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Does not salvage the protective effects of ACE2 inhibited by SARS-CoV-2
Dry cough is common side effect May not be effective in tissues with
high Chymase expression (e.g., heart) Challenges with drug interactions,
hypotensive patients, other side effects\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Potential for rapid (compassionate) use in at-risk patients and for
rapid (repurposing) clinical trials.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Angiotensin Receptor Blockers (ARBs)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mitigates effects of ANG II (via AGTR1) in relevant cell types/tissues
involved in COVID-19 pathobiology Long track record of clinical use Well
defined PK and PD Large amount of preclinical animal data Oral
administration. Possible inhalable administration Generic Drugs, with
established production, supply chain and handling\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Does not salvage the protective effects of ACE2 inhibited by SARS-CoV-2
Challenges with drug interactions, hypotensive patients, other side
effects Will not impede possible pathological effects of AGTR2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Potential for rapid (compassionate) use in at-risk patients and for
rapid (repurposing) clinical trials.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Recombinant soluble ACE2}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
`Rescues' ACE2 activity inhibited by SARS-CoV-2 infection via action as
a `decoy' for the virus Mitigates effects of ANG II in relevant cell
types/tissues involved in COVID-19 pathobiology Substantial preclinical
data in animals\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Limited data from human studies; unknowns regarding safety Limited
information regarding dosing, target engagement, PK, PD etc. Higher
costs + more complicated handling, new supply chain Infusion is
required\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Additional preclinical studies needed, in parallel with early-phase
trials\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ANG (1-7)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Engages protective MAS1 signaling, mitigating harmful effects of ACE2
inhibition by SARS-CoV-2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Very limited data from human studies Less available preclinical data
than for the other options Limited information regarding dosing, target
engagement, PK, PD etc., all Indirectly inhibits pathological ANG II
signaling Higher costs + more complicated handling, new supply chain
Infusion is required\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Additional preclinical studies needed. Unclear that human trials are
justified.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1} . \textbf{The pros and cons of different tools for
targeting the RAS pathway. PK: Pharmacokinetics; PD: Pharmacodynamics}



\textbf{Summary and Conclusions}

The COVID-19 pandemic has sparked an urgent search for effective
therapeutics, with little clear success at the time we have prepared
this article (early April, 2020). Targeting the RAS pathway has received
limited attention even though it is an important component of COVID-19
pathobiology with implications for therapeutics that could ameliorate
tissue injury, disease progression and improve morbidity and mortality.
A key reason for the limited attention on the RAS system as a
therapeutic target may stem from the lack of mechanistic insight
regarding the potential benefit of targeting this pathway.

To address this gap, we propose an overriding hypothesis:\emph{imbalance
of ACE1- and ACE2-mediated signaling as a primary driver of tissue
pathobiology in COVID-19, impacting the phenotypes of multiple
interacting cell types in infected tissue, leading to feedback loops
that promote inflammation and injury} . Tissue damage from the infection
is a consequence of enhanced ANG II/AGTR1 signaling and decreased
signaling by ANG (1-7) and perhaps other ACE2-derived peptides. In the
lungs and heart (\textbf{Figures 3, 5} ), the imbalance in the RAS
pathway and positive feedback loops can establish a vicious cycle of
events mediated by communication among cell types that produce COVID-19
pathology. Similar mechanisms may also occur in other organs.

Numerous studies and findings corroborate this hypothesis, including
results from animal models, clinical data in humans and in-vitro
findings with human and rodent cells. Moreover, it provides a
parsimonious explanation for key features of the disease and for the
contribution of comorbidities to adverse outcomes in COVID-19.

The hypothesis also leads to several testable predictions for COVID-19:
a) susceptibility for adverse outcomes in those with specific ACE1
genotypes and perhaps other genetic variants in RAS pathway elements; b)
potential for patients with a range of illnesses to have worse outcomes;
c) adjusting for other clinical variables, patients administered ARBs
(and perhaps ACEIs) should have improved outcomes; d) counteracting the
imbalance in RAS signaling with agents discussed above should modulate
clinicopathological effects of the SARS-CoV-2 virus; e) early
administration of RAS-targeted agents may yield maximum benefit,
preventing ALI and ARDS by mitigating the damage from the imbalance in
ACE1- and ACE2-derived peptides and their signaling.

Given the severity of the COVID-19 crisis, what types of studies
(besides clinical trials) might help test our hypothesis? We envisage
several possibilities: a) in-vitro studies using human alveolar
epithelial cells, perhaps in 3-D organoid models in co-cultures with
other key cell types (e.g. fibroblasts, endothelial cells, immune cells)
to determine if cellular injury by SARS-CoV-2 infection is inhibited by
ACEIs/ARBs/soluble ACE2. Monteil et al., (2020) have demonstrated
efficacy of recombinant ACE2 in blunting infectivity of SARS-CoV-2 in
such models but more detailed analyses and further studies are needed.
b) In vivo studies to test efficacy of ACEIs/ARBs/soluble ACE2 in animal
models {[}e.g., mice, ferrets and rhesus monkeys, with preference for
primate models, e.g., Sutton \& Subbarao, (2015); Gretebeck \& Subbarao,
(2015){]} of SARS-1 infection. Ferrets may be useful to assess
SARS-CoV-2 infectivity but infected animals appear to have few
pathological features (Shi et al., 2020); rhesus monkeys with SARS-CoV-2
infection also show signs of clinical disease (Bao et al., 2020). c)
epidemiological data from COVID-19 patients to define associations
between ACEI/ARB use/dose and disease severity/mortality. Certain data
of this type have been obtained (Liu et al., 2020) but more are needed,
especially because of confounding factors in such analyses, including
comorbidities relevant to COVID-19. A multi-country database that
assessed usage of ARBs and ACEIs prior to hospital admission with
clinical outcomes from COVID-19 might be very helpful for such analyses
and to define possible differences from patients in different countries.

The hypothesis thus implies that those being treated for approved
indications with ACEIs and ARBS should maintain their use of these drugs
and in addition, that those drugs may have therapeutic utility in
treating patients who develop COVID-19, in particular those most
vulnerable to this viral infection (e.g., those \textgreater{}70 years
old and/or with comorbidities). ACEIs and ARBs have well known safety
profiles, making these drugs well-suited for repurposing. In addition, a
rationale exists for testing the possible therapeutic effects of soluble
ACE2 or perhaps ACE2 peptides. The current and likely future challenge
of treating seriously ill COVID-19 patients argues for aggressive
approaches. We urge that these approaches include ones that seek to
restore ACE1/ACE2 imbalance.

\emph{Declaration of transparency and scientific rigour}

This Declaration acknowledges that this paper adheres to the principles
for transparent reporting and scientific rigour of preclinical research
as stated in the BJP guidelines for Design \& Analysis, and as
recommended by funding agencies, publishers and other organisations
engaged with supporting research.



\textbf{References}

\begin{enumerate}
\tightlist
\item
  Adamzik, M., Frey, U., Sixt, S., Knemeyer, L., Beiderlinden, M.,
  Peters, J., \& Siffert, W. (2007). ACE I/D but not AGT (-6) A/G
  polymorphism is a risk factor for mortality in ARDS. European
  Respiratory Journal, 29(3), 482-488.
\item
  Adedeji, A. O., \& Sarafianos, S. G. (2014). Antiviral drugs specific
  for coronaviruses in preclinical development. Current opinion in
  virology, 8, 45-53.
\item
  Adedeji, A. O., Severson, W., Jonsson, C., Singh, K., Weiss, S. R., \&
  Sarafianos, S. G. (2013). Novel inhibitors of severe acute respiratory
  syndrome coronavirus entry that act by three distinct mechanisms.
  Journal of virology, 87(14), 8017-8028.
\item
  Alexander, S. P., Battey, J., Benson, H. E., Benya, R. V., Bonner, T.
  I., Davenport, A. P., \ldots{} \& Karnik, S. (2019). Class A Orphans
  (version 2019.5) in the IUPHAR/BPS Guide to Pharmacology Database.
  IUPHAR/BPS Guide to Pharmacology CITE, 2019(5).
\item
  Andreeva, A. V., Kutuzov, M. A., \& Voyno-Yasenetskaya, T. A. (2007).
  Regulation of surfactant secretion in alveolar type II cells. American
  Journal of Physiology-Lung Cellular and Molecular Physiology, 293(2),
  L259-L271.
\item
  Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J.,
  Southan, C., Sharman, J. L., \ldots{} \& Spedding, M. (2020). The
  IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology
  content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY.
  Nucleic acids research, 48(D1), D1006-D1021.
\item
  Arumugam, S., Sreedhar, R., Thandavarayan, R. A., Karuppagounder, V.,
  Krishnamurthy, P., Suzuki, K., \ldots{} \& Watanabe, K. (2016).
  Angiotensin receptor blockers: Focus on cardiac and renal injury.
  Trends in cardiovascular medicine, 26(3), 221-228.
\item
  Attaway, A. H., Myers, C., Velani, S., \& Schilz, R. (2017). Inhaled
  Prostacyclin as Salvage Therapy for ARDS: Can We Find the Right
  Patient?
\item
  Aumiller, V., Balsara, N., Wilhelm, J., G\selectlanguage{ngerman}ünther, A., \& Königshoff, M.
  (2013). WNT/\selectlanguage{greek}β-\selectlanguage{english}catenin signaling induces IL-1\selectlanguage{greek}β \selectlanguage{english}expression by alveolar
  epithelial cells in pulmonary fibrosis. American journal of
  respiratory cell and molecular biology, 49(1), 96-104.
\item
  Baker, K. M., Booz, G. W., \& Dostal, D. E. (1992). Cardiac actions of
  angiotensin II: role of an intracardiac renin-angiotensin system.
  Annual review of physiology, 54(1), 227-241.
\item
  Bao, L., Deng, W., Gao, H., Xiao, C., Liu, J., Xue, J., \ldots{} \&
  Qi, F. (2020). Reinfection could not occur in SARS-CoV-2 infected
  rhesus macaques. bioRxiv. doi:
  https://doi.org/10.1101/2020.03.13.990226
\item
  Bar-On, Y. M., Flamholz, A., Phillips, R., \& Milo, R. (2020).
  SARS-CoV-2 (COVID-19) by the numbers. eLife, 9, e57309.
\item
  Barroso, L. C., Magalhaes, G. S., Galv\selectlanguage{ngerman}ão, I., Reis, A. C., Souza, D.
  G., Sousa, L. P., \ldots{} \& Teixeira, M. M. (2017).
  Angiotensin-(1-7) promotes resolution of neutrophilic inflammation in
  a model of antigen-induced arthritis in mice. Frontiers in immunology,
  8, 1596.
\item
  Bechara, R. I., Brown, L. A. S., Eaton, D. C., Roman, J., \& Guidot,
  D. M. (2003). Chronic ethanol ingestion increases expression of the
  angiotensin II type 2 (AT2) receptor and enhances tumor necrosis
  factor\selectlanguage{english}-\selectlanguage{greek}α\selectlanguage{english}-\selectlanguage{english}and angiotensin II-induced cytotoxicity via AT2 signaling in
  rat alveolar epithelial cells. Alcoholism: Clinical and Experimental
  Research, 27(6), 1006-1014.
\item
  Becker, L. K., Totou, N., Moura, S., Kangussu, L., Mill\selectlanguage{ngerman}án, R. D. S.,
  Campagnole-Santos, M. J., \ldots{} \& Santos, R. A. S. (2018).
  Eccentric overload muscle damage is attenuated by a novel
  angiotensin-(1-7) treatment. International journal of sports medicine,
  39(10), 743-748.
\item
  Bhattacharya, J., \& Westphalen, K. (2016, July).
  Macrophage-epithelial interactions in pulmonary alveoli. In Seminars
  in immunopathology (Vol. 38, No. 4, pp. 461-469). Springer Berlin
  Heidelberg.
\item
  Bodor, C., Nagy, J. P., Végh, B., Németh, A., Jenei, A.,
  MirzaHosseini, S., \ldots{} \& Rosivall, L. (2012). Angiotensin II
  increases the permeability and PV-1 expression of endothelial cells.
  American Journal of Physiology-Cell Physiology, 302(1), C267-C276.
\item
  Boskabadi, J., Askari, V. R., Hosseini, M., \& Boskabady, M. H.
  (2019). Immunomodulatory properties of captopril, an ACE inhibitor, on
  LPS-induced lung inflammation and fibrosis as well as oxidative
  stress. Inflammopharmacology, 27(3), 639-647.
\item
  Bozkurt, B., Kovacs, R., \& Harrington, B. (2020). HFSA/ACC/AHA
  Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19.
  American Heart Association Professional Heart Daily.
\item
  Buckley, S. T., Medina, C., \& Ehrhardt, C. (2010). Differential
  susceptibility to epithelial-mesenchymal transition (EMT) of alveolar,
  bronchial and intestinal epithelial cells in vitro and the effect of
  angiotensin II receptor inhibition. Cell and tissue research, 342(1),
  39-51.
\item
  Caldeira, D., Alarcão, J., Vaz-Carneiro, A., \& Costa, J. (2012). Risk
  of pneumonia associated with use of angiotensin converting enzyme
  inhibitors and angiotensin receptor blockers: systematic review and
  meta-analysis. Bmj, 345, e4260.
\item
  Castelo-Branco, C., \& Soveral, I. (2014). The immune system and
  aging: a review. Gynecological Endocrinology, 30(1), 16-22.
\item
  Channappanavar, R., \& Perlman, S. (2017, July). Pathogenic human
  coronavirus infections: causes and consequences of cytokine storm and
  immunopathology. In Seminars in immunopathology (Vol. 39, No. 5, pp.
  529-539). Springer Berlin Heidelberg.
\item
  Channappanavar, R., Zhao, J., \& Perlman, S. (2014). T cell-mediated
  immune response to respiratory coronaviruses. Immunologic research,
  59(1-3), 118-128.
\item
  Chen, C., Zhang, Z., Li, Z., Zhang, F., Peng, M., Chen, Y., \& Wang,
  Y. (2014). Losartan attenuates microvascular permeability in
  mechanical ventilator-induced lung injury in diabetic mice. Molecular
  biology reports, 41(2), 809-814.
\item
  Chen, C., Zhou, Y., \& Wang, D. W. (2020). SARS-CoV-2: a potential
  novel etiology of fulminant myocarditis. Herz, 1-3.
\item
  Chuquimia, O. D., Petursdottir, D. H., Rahman, M. J., Hartl, K.,
  Singh, M., \& Fernández, C. (2012). The role of alveolar epithelial
  cells in initiating and shaping pulmonary immune responses:
  communication between innate and adaptive immune systems. PloS one,
  7(2).
\item
  Cohen, E. P., Bedi, M., Irving, A. A., Jacobs, E., Tomic, R., Klein,
  J., \ldots{} \& Moulder, J. E. (2012). Mitigation of late renal and
  pulmonary injury after hematopoietic stem cell transplantation.
  International Journal of Radiation Oncology* Biology* Physics, 83(1),
  292-296.
\item
  da Silveira, K. D., Coelho, F. M., Vieira, A. T., Sachs, D., Barroso,
  L. C., Costa, V. V., \ldots{} \& dos Santos, R. A. S. (2010).
  Anti-inflammatory effects of the activation of the angiotensin-(1--7)
  receptor, MAS, in experimental models of arthritis. The Journal of
  Immunology, 185(9), 5569-5576.
\item
  De Mello, W. C., \& Danser, A. J. (2000). Angiotensin II and the
  heart: on the intracrine renin-angiotensin system. Hypertension,
  35(6), 1183-1188.
\item
  Deng, J., Wang, D. X., Deng, W., Li, C. Y., \& Tong, J. (2012a). The
  effect of endogenous angiotensin II on alveolar fluid clearance in
  rats with acute lung injury. Canadian respiratory journal, 19(5),
  311-318.
\item
  Deng, J., Wang, D. X., Deng, W., Li, C. Y., Tong, J., \& Ma, H.
  (2012b). Regulation of alveolar fluid clearance and ENaC expression in
  lung by exogenous angiotensin II. Respiratory physiology \&
  neurobiology, 181(1), 53-61.
\item
  Dhama, K.; Patel, S.K.; Pathak, M.; Yatoo, M.I.; Tiwari, R.; \ldots{}
  \& Rodriguez-Morales, A.J. An Update on SARS-COV-2/COVID-19 with
  Particular Reference on Its Clinical Pathology, Pathogenesis,
  Immunopathology and Mitigation Strategies -- A Review. Preprints 2020,
  2020030348 (doi: 10.20944/preprints202003.0348.v1)
\item
  Dijkman, R., Jebbink, M. F., Deijs, M., Milewska, A., Pyrc, K.,
  Buelow, E., \ldots{} \& van der Hoek, L. (2012). Replication-dependent
  downregulation of cellular angiotensin-converting enzyme 2 protein
  expression by human coronavirus NL63. Journal of general virology,
  93(9), 1924-1929.
\item
  Donath, M. Y., Meier, D. T., \& Böni-Schnetzler, M. (2019).
  Inflammation in the pathophysiology and therapy of cardiometabolic
  disease. Endocrine reviews, 40(4), 1080-1091.
\item
  Dostal, D. E., \& Baker, K. M. (1999). The cardiac renin-angiotensin
  system: conceptual, or a regulator of cardiac function?. Circulation
  research, 85(7), 643-650.
\item
  Du, Y., Tu, L., Zhu, P., Mu, M., Wang, R., Yang, P., \ldots{} \& Li,
  T. (2020). Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan:
  A Retrospective Observational Study. American Journal of Respiratory
  and Critical Care Medicine, (ja).
\item
  Eisele, N. A., \& Anderson, D. M. (2011). Host defense and the airway
  epithelium: frontline responses that protect against bacterial
  invasion and pneumonia. Journal of pathogens, 2011.
\item
  Fang, L., Karakiulakis, G., \& Roth, M. (2020). Are patients with
  hypertension and diabetes mellitus at increased risk for COVID-19
  infection? The Lancet Respiratory Medicine. 8(4), PE-21
\item
  Ferrucci, L., \& Fabbri, E. (2018). Inflammageing: chronic
  inflammation in ageing, cardiovascular disease, and frailty. Nature
  Reviews Cardiology, 15(9), 505-522.
\item
  Flores\selectlanguage{english}-Munoz, M., Smith, N. J., Haggerty, C., Milligan, G., \&
  Nicklin, S. A. (2011). Angiotensin1\selectlanguage{english}-9 antagonises pro\selectlanguage{english}-hypertrophic
  signalling in cardiomyocytes via the angiotensin type 2 receptor. The
  journal of Physiology, 589(4), 939-951.
\item
  Florez\selectlanguage{english}-Sampedro, L., Song, S., \& Melgert, B. N. (2018). The diversity
  of myeloid immune cells shaping wound repair and fibrosis in the lung.
  Regeneration, 5(1), 3-25.
\item
  Forrester, S. J., Booz, G. W., Sigmund, C. D., Coffman, T. M., Kawai,
  T., Rizzo, V., \ldots{} \& Eguchi, S. (2018). Angiotensin II signal
  transduction: an update on mechanisms of physiology and
  pathophysiology. Physiological reviews, 98(3), 1627-1738.
\item
  Frieler, R. A., \& Mortensen, R. M. (2015). Immune cell and other
  noncardiomyocyte regulation of cardiac hypertrophy and remodeling.
  Circulation, 131(11), 1019-1030.
\item
  Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E. H., Cohen, A.
  A., \ldots{} \& Franceschi, C. (2018). Immunosenescence and
  inflamm-aging as two sides of the same coin: friends or foes?.
  Frontiers in immunology, 8, 1960.
\item
  Gard, P. R. (2010). Implications of the angiotensin converting enzyme
  gene insertion/deletion polymorphism in health and disease: a snapshot
  review. International journal of molecular epidemiology and genetics,
  1(2), 145.
\item
  Gautret, P., Lagier, J. C., Parola, P., Meddeb, L., Mailhe, M.,
  Doudier, B., \ldots{} \& Honore, S. (2020). Hydroxychloroquine and
  azithromycin as a treatment of COVID-19: results of an open-label
  non-randomized clinical trial. International Journal of Antimicrobial
  Agents, 105949.
\item
  Glowacka, I., Bertram, S., Herzog, P., Pfefferle, S., Steffen, I.,
  Muench, M. O., \ldots{} \& Eichler, J. (2010). Differential
  downregulation of ACE2 by the spike proteins of severe acute
  respiratory syndrome coronavirus and human coronavirus NL63. Journal
  of virology, 84(2), 1198-1205.
\item
  Godugu, C., Patel, A. R., Doddapaneni, R., Marepally, S., Jackson, T.,
  \& Singh, M. (2013). Inhalation delivery of Telmisartan enhances
  intratumoral distribution of nanoparticles in lung cancer models.
  Journal of controlled release, 172(1), 86-95.
\item
  Gralinski, L. E., \& Baric, R. S. (2015). Molecular pathology of
  emerging coronavirus infections. The Journal of pathology, 235(2),
  185-195.
\item
  Gretebeck, L. M., \& Subbarao, K. (2015). Animal models for SARS and
  MERS coronaviruses. Current opinion in virology, 13, 123-129.
\item
  Grommes, J., \& Soehnlein, O. (2011). Contribution of neutrophils to
  acute lung injury. Molecular medicine, 17(3), 293.
\item
  Gu, J., Han, B., \& Wang, J. (2020). COVID-19: Gastrointestinal
  manifestations and potential fecal-oral transmission.
  Gastroenterology.
\item
  Guo, T., Fan, Y., Chen, M., Wu, X., Zhang, L., He, T., \ldots{} \& Lu,
  Z. (2020). Cardiovascular implications of fatal outcomes of patients
  with coronavirus disease 2019 (COVID-19). JAMA cardiology.
\item
  Haga, S., Yamamoto, N., Nakai-Murakami, C., Osawa, Y., Tokunaga, K.,
  Sata, T., \ldots{} \& Ishizaka, Y. (2008). Modulation of
  TNF-\selectlanguage{greek}α-\selectlanguage{english}converting enzyme by the spike protein of SARS-CoV and ACE2
  induces TNF-\selectlanguage{greek}α \selectlanguage{english}production and facilitates viral entry. Proceedings of
  the National Academy of Sciences, 105(22), 7809-7814.
\item
  Hammer, A., Yang, G., Friedrich, J., Kovacs, A., Lee, D. H., Grave,
  K., \ldots{} \& Gold, R. (2016). Role of the receptor Mas in
  macrophage-mediated inflammation in vivo. Proceedings of the National
  Academy of Sciences, 113(49), 14109-14114.
\item
  Hamming, I., Timens, W., Bulthuis, M. L. C., Lely, A. T., Navis, G.
  J., \& van Goor, H. (2004). Tissue distribution of ACE2 protein, the
  functional receptor for SARS coronavirus. A first step in
  understanding SARS pathogenesis. The Journal of Pathology: A Journal
  of the Pathological Society of Great Britain and Ireland, 203(2),
  631-637.
\item
  Han, D. P., Penn-Nicholson, A., \& Cho, M. W. (2006). Identification
  of critical determinants on ACE2 for SARS-CoV entry and development of
  a potent entry inhibitor. Virology, 350(1), 15-25.
\item
  Han, S. X., He, G. M., Wang, T., Chen, L., Ning, Y. Y., Luo, F.,
  \ldots{} \& Xu, D. (2010). Losartan attenuates chronic cigarette smoke
  exposure-induced pulmonary arterial hypertension in rats: possible
  involvement of angiotensin-converting enzyme-2. Toxicology and applied
  pharmacology, 245(1), 100-107.
\item
  Harder, E. M., Park, H. S., Nath, S. K., Mancini, B. R., \& Decker, R.
  H. (2015). Angiotensin-converting enzyme inhibitors decrease the risk
  of radiation pneumonitis after stereotactic body radiation therapy.
  Practical radiation oncology, 5(6), e643-e649.
\item
  He, F., Deng, Y., \& Li, W. (2020). Coronavirus Disease 2019
  (COVID-19): What we know?. Journal of Medical Virology.
\item
  He, H., Liu, L., Chen, Q., Liu, A., Cai, S., Yang, Y., \ldots{} \&
  Qiu, H. (2015). Mesenchymal stem cells overexpressing
  angiotensin-converting enzyme 2 rescue lipopolysaccharide-induced lung
  injury. Cell transplantation, 24(9), 1699-1715.
\item
  He, X., Han, B., Mura, M., Xia, S., Wang, S., Ma, T., \ldots{} \& Liu,
  Z. (2007). Angiotensin-converting enzyme inhibitor captopril prevents
  oleic acid-induced severe acute lung injury in rats. Shock, 28(1),
  106-111.
\item
  Herold, S., Ludwig, S., Pleschka, S., \& Wolff, T. (2012). Apoptosis
  signaling in influenza virus propagation, innate host defense, and
  lung injury. Journal of leukocyte biology, 92(1), 75-82.
\item
  Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., \ldots{} \&
  Cheng, Z. (2020). Clinical features of patients infected with 2019
  novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497-506.
\item
  Hui, D. S., Joynt, G. M., Wong, K. T., Gomersall, C. D., Li, T. S.,
  Antonio, G., \ldots{} \& Rainer, T. H. (2005). Impact of severe acute
  respiratory syndrome (SARS) on pulmonary function, functional capacity
  and quality of life in a cohort of survivors. Thorax, 60(5), 401-409.
\item
  Hung, I. F. N., Cheng, V. C. C., Wu, A. K. L., Tang, B. S. F., Chan,
  K. H., Chu, C. M., \ldots{} \& Chan, K. S. (2004). Viral loads in
  clinical specimens and SARS manifestations. Emerging infectious
  diseases, 10(9), 1550.
\item
  Imai, Y., Kuba, K., Rao, S., Huan, Y., Guo, F., Guan, B., \ldots{} \&
  Crackower, M. A. (2005). Angiotensin-converting enzyme 2 protects from
  severe acute lung failure. Nature, 436(7047), 112-116.
\item
  Inoue, Y., Tanaka, N., Tanaka, Y., Inoue, S., Morita, K., Zhuang, M.,
  \ldots{} \& Sugamura, K. (2007). Clathrin-dependent entry of severe
  acute respiratory syndrome coronavirus into target cells expressing
  ACE2 with the cytoplasmic tail deleted. Journal of virology, 81(16),
  8722-8729.
\item
  Ismael-Badarneh, R., Guetta, J., Klorin, G., Berger, G., Abu-saleh,
  N., Abassi, Z., \& Azzam, Z. S. (2015). The role of angiotensin II and
  cyclic AMP in alveolar active sodium transport. PloS one, 10(7).
\item
  Itoyama, S., Keicho, N., Quy, T., Phi, N. C., Long, H. T., Van Ban,
  V., \ldots{} \& Yanai, H. (2004). ACE1 polymorphism and progression of
  SARS. Biochemical and biophysical research communications, 323(3),
  1124-1129.
\item
  Jerng, J. S., Hsu, Y. C., Wu, H. D., Pan, H. Z., Wang, H. C., Shun, C.
  T., \ldots{} \& Yang, P. C. (2007). Role of the renin-angiotensin
  system in ventilator-induced lung injury: an in vivo study in a rat
  model. Thorax, 62(6), 527-535.
\item
  Jiang, J. S., Wang, L. F., Chou, H. C., \& Chen, C. M. (2007).
  Angiotensin-converting enzyme inhibitor captopril attenuates
  ventilator-induced lung injury in rats. Journal of applied physiology,
  102(6), 2098-2103.
\item
  Jones, E. S., Vinh, A., McCarthy, C. A., Gaspari, T. A., \& Widdop, R.
  E. (2008). AT2 receptors: functional relevance in cardiovascular
  disease. Pharmacology \& therapeutics, 120(3), 292-316.
\item
  Kam, K. Q., Yung, C. F., Cui, L., Tzer Pin Lin, R., Mak, T. M.,
  Maiwald, M., \ldots{} \& Thoon, K. C. (2020). A Well Infant with
  Coronavirus Disease 2019 with High Viral Load. Clinical Infectious
  Diseases.
\item
  Karnik, S. S., Singh, K. D., Tirupula, K., \& Unal, H. (2017).
  Significance of angiotensin 1--7 coupling with MAS1 receptor and other
  GPCRs to the renin-angiotensin system: IUPHAR Review 22. British
  journal of pharmacology, 174(9), 737-753.
\item
  Kaschina, E., \& Unger, T. (2003). Angiotensin AT1/AT2 receptors:
  regulation, signalling and function. Blood pressure, 12(2), 70-88.
\item
  Ketai, L., Paul, N. S., \& Ka-tak, T. W. (2006). Radiology of severe
  acute respiratory syndrome (SARS): the emerging pathologic-radiologic
  correlates of an emerging disease. Journal of thoracic imaging, 21(4),
  276-283.
\item
  Khan, A., Benthin, C., Zeno, B., Albertson, T. E., Boyd, J., Christie,
  J. D., \ldots{} \& Hardes, K. (2017). A pilot clinical trial of
  recombinant human angiotensin-converting enzyme 2 in acute respiratory
  distress syndrome. Critical Care, 21(1), 234.
\item
  Khan, A., Benthin, C., Zeno, B., Albertson, T. E., Boyd, J., Christie,
  J. D., \ldots{} \& Hardes, K. (2017). A pilot clinical trial of
  recombinant human angiotensin-converting enzyme 2 in acute respiratory
  distress syndrome. Critical Care, 21(1), 234.
\item
  Kharofa, J., Cohen, E. P., Tomic, R., Xiang, Q., \& Gore, E. (2012).
  Decreased risk of radiation pneumonitis with incidental concurrent use
  of angiotensin-converting enzyme inhibitors and thoracic radiation
  therapy. International Journal of Radiation Oncology* Biology*
  Physics, 84(1), 238-243.
\item
  Kim, M. D., Baumlin, N., Yoshida, M., Polineni, D., Salathe, S. F.,
  David, J. K., \ldots{} \& Whitney, P. (2020). Losartan rescues
  inflammation-related mucociliary dysfunction in relevant models of
  cystic fibrosis. American journal of respiratory and critical care
  medicine, 201(3), 313-324.
\item
  Kode, A., Yang, S. R., \& Rahman, I. (2006). Differential effects of
  cigarette smoke on oxidative stress and proinflammatory cytokine
  release in primary human airway epithelial cells and in a variety of
  transformed alveolar epithelial cells. Respiratory research, 7(1),
  132.
\item
  Konigshoff, M., Wilhelm, A., Jahn, A., Sedding, D., Amarie, O. V.,
  Eul, B., \ldots{} \& Rose, F. (2007). The angiotensin II receptor 2 is
  expressed and mediates angiotensin II signaling in lung fibrosis.
  American journal of respiratory cell and molecular biology, 37(6),
  640-650.
\item
  Kruse, R. L. (2020). Therapeutic strategies in an outbreak scenario to
  treat the novel coronavirus originating in Wuhan, China.
  F1000Research, 9.
\item
  Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., \ldots{} \&
  Bao, L. (2005). A crucial role of angiotensin converting enzyme 2
  (ACE2) in SARS coronavirus--induced lung injury. Nature medicine,
  11(8), 875-879.
\item
  Kuba, K., Imai, Y., Rao, S., Jiang, C., \& Penninger, J. M. (2006).
  Lessons from SARS: control of acute lung failure by the SARS receptor
  ACE2. Journal of molecular medicine, 84(10), 814-820.
\item
  Kurdi, M., \& Booz, G. W. (2011). New take on the role of angiotensin
  II in cardiac hypertrophy and fibrosis. Hypertension, 57(6),
  1034-1038.
\item
  Lambert, D. W., Yarski, M., Warner, F. J., Thornhill, P., Parkin, E.
  T., Smith, A. I., \ldots{} \& Turner, A. J. (2005). Tumor necrosis
  factor-\selectlanguage{greek}α \selectlanguage{english}convertase (ADAM17) mediates regulated ectodomain shedding of
  the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor,
  angiotensin-converting enzyme-2 (ACE2). Journal of Biological
  Chemistry, 280(34), 30113-30119.
\item
  Lee, J. H., Kim, J. H., Kim, J. S., Chang, J. W., Kim, S. B., Park, J.
  S., \& Lee, S. K. (2013). AMP-activated protein kinase inhibits
  TGF-\selectlanguage{greek}β-, \selectlanguage{english}angiotensin II-, aldosterone-, high glucose-, and
  albumin-induced epithelial-mesenchymal transition. American Journal of
  Physiology-Renal Physiology, 304(6), F686-F697.
\item
  Lee, Y. H., Mungunsukh, O., Tutino, R. L., Marquez, A. P., \& Day, R.
  M. (2010). Angiotensin-II-induced apoptosis requires regulation of
  nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells.
  Journal of cell science, 123(10), 1634-1643.
\item
  Lemari\selectlanguage{ngerman}é, C. A., \& Schiffrin, E. L. (2010). The angiotensin II type 2
  receptor in cardiovascular disease. Journal of the
  renin-angiotensin-aldosterone system, 11(1), 19-31.
\item
  Li, C. K. F., Wu, H., Yan, H., Ma, S., Wang, L., Zhang, M., \ldots{}
  \& Douek, D. C. (2008). T cell responses to whole SARS coronavirus in
  humans. The Journal of Immunology, 181(8), 5490-5500.
\item
  Li, G., Fan, Y., Lai, Y., Han, T., Li, Z., Zhou, P., \ldots{} \&
  Zhang, Q. (2020). Coronavirus infections and immune responses. Journal
  of medical virology, 92(4), 424-432.
\item
  Li, X., Molina-Molina, M., Abdul-Hafez, A., Uhal, V., Xaubet, A., \&
  Uhal, B. D. (2008b). Angiotensin converting enzyme-2 is protective but
  downregulated in human and experimental lung fibrosis. American
  Journal of Physiology-Lung Cellular and Molecular Physiology, 295(1),
  L178-L185.
\item
  Li, X., Rayford, H., \& Uhal, B. D. (2003). Essential roles for
  angiotensin receptor AT1a in bleomycin-induced apoptosis and lung
  fibrosis in mice. The American journal of pathology, 163(6),
  2523-2530.
\item
  Li, X., Zhuang, J., Rayford, H., Zhang, H., Shu, R., \& Uhal, B. D.
  (2007). Attenuation of bleomycin-induced pulmonary fibrosis by
  intratracheal administration of antisense oligonucleotides against
  angiotensinogen mRNA. Current pharmaceutical design, 13(12),
  1257-1268.
\item
  Li, Y., Zeng, Z., Li, Y., Huang, W., Zhou, M., Zhang, X., \& Jiang, W.
  (2015). Angiotensin-converting enzyme inhibition attenuates
  lipopolysaccharide-induced lung injury by regulating the balance
  between angiotensin-converting enzyme and angiotensin-converting
  enzyme 2 and inhibiting mitogen-activated protein kinase activation.
  Shock, 43(4), 395-404.
\item
  Liu, J., Zhang, P. S., Yu, Q., Liu, L., Yang, Y., Guo, F. M., \& Qiu,
  H. B. (2012). Losartan inhibits conventional dendritic cell maturation
  and Th1 and Th17 polarization responses: \selectlanguage{greek}Ν\selectlanguage{english}ovel mechanisms of
  preventive effects on lipopolysaccharide-induced acute lung injury.
  International journal of molecular medicine, 29(2), 269-276.
\item
  Liu, P., Wysocki, J., Souma, T., Ye, M., Ramirez, V., Zhou, B.,
  \ldots{} \& Jin, J. (2018). Novel ACE2-Fc chimeric fusion provides
  long-lasting hypertension control and organ protection in mouse models
  of systemic renin angiotensin system activation. Kidney international,
  94(1), 114-125.
\item
  Liu, Y., Huang, F., Xu, J., Yang, P., Qin, Y., Cao, M., \ldots{} \&
  Lv, J. (2020). Anti-hypertensive Angiotensin II receptor blockers
  associated to mitigation of disease severity in elderly COVID-19
  patients. medRxiv. doi: https://doi.org/10.1101/2020.03.20.20039586
\item
  Liu, Y., Yang, Y., Zhang, C., Huang, F., Wang, F., Yuan, J., \ldots{}
  \& Zhang, Z. (2020b). Clinical and biochemical indexes from 2019-nCoV
  infected patients linked to viral loads and lung injury. Science China
  Life Sciences, 63(3), 364-374.
\item
  Lukkarinen, H. P., Laine, J., Aho, H., Zagariya, A., Vidyasagar, D.,
  \& K\selectlanguage{ngerman}ääpä, P. O. (2005). Angiotensin II receptor inhibition prevents
  pneumocyte apoptosis in surfactant\selectlanguage{english}-depleted rat lungs. Pediatric
  pulmonology, 39(4), 349-358.
\item
  Luo, W., Yu, H., Gou, J., Li, X., Sun, Y., Li, J., \& Liu, L. (2020).
  Clinical pathology of critical patient with novel coronavirus
  pneumonia (COVID-19). Pathology \& Pathobiology, 2020020407.
\item
  Ma, X., Xu, D., Ai, Y., Ming, G., \& Zhao, S. (2010). Fas inhibition
  attenuates lipopolysaccharide-induced apoptosis and cytokine release
  of rat type II alveolar epithelial cells. Molecular biology reports,
  37(7), 3051-3056.
\item
  Magalhaes, G. S., Rodrigues-Machado, M. G., Motta-Santos, D., Alenina,
  N., Bader, M., Santos, R. A., \ldots{} \& Campagnole-Santos, M. J.
  (2016). Chronic allergic pulmonary inflammation is aggravated in
  angiotensin-(1--7) Mas receptor knockout mice. American Journal of
  Physiology-Lung Cellular and Molecular Physiology, 311(6),
  L1141-L1148.
\item
  Mancini, G. J., Etminan, M., Zhang, B., Levesque, L. E., FitzGerald,
  J. M., \& Brophy, J. M. (2006). Reduction of morbidity and mortality
  by statins, angiotensin-converting enzyme inhibitors, and angiotensin
  receptor blockers in patients with chronic obstructive pulmonary
  disease. Journal of the American College of Cardiology, 47(12),
  2554-2560.
\item
  Marshall, R. P., McANULTY, R. J., \& Laurent, G. J. (2000).
  Angiotensin II is mitogenic for human lung fibroblasts via activation
  of the type 1 receptor. American journal of respiratory and critical
  care medicine, 161(6), 1999-2004.
\item
  Medhora, M., Gao, F., Jacobs, E. R., \& Moulder, J. E. (2012).
  Radiation damage to the lung: Mitigation by angiotensin\selectlanguage{english}-converting
  enzyme (ACE) inhibitors. Respirology, 17(1), 66-71.
\item
  Meng, Y., Li, T., Zhou, G. S., Chen, Y., Yu, C. H., Pang, M. X.,
  \ldots{} \& Li, X. (2015). The angiotensin-converting enzyme
  2/angiotensin (1--7)/Mas axis protects against lung fibroblast
  migration and lung fibrosis by inhibiting the NOX4-derived
  ROS-mediated RhoA/Rho kinase pathway. Antioxidants \& redox signaling,
  22(3), 241-258.
\item
  Meng, Y., Yu, C. H., Li, W., Li, T., Luo, W., Huang, S., \ldots{} \&
  Li, X. (2014). Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas
  axis protects against lung fibrosis by inhibiting the MAPK/NF-\selectlanguage{greek}κ\selectlanguage{english}B
  pathway. American journal of respiratory cell and molecular biology,
  50(4), 723-736.
\item
  Mohammadi-Karakani, A., Ghazi-Khansari, M., \& Sotoudeh, M. (2006).
  Lisinopril ameliorates paraquat-induced lung fibrosis. Clinica chimica
  acta, 367(1-2), 170-174.
\item
  Molteni, A., Wolfe, L. F., Ward, W. F., Hsin Ts' ao, C., Brizio
  Molteni, L., Veno, P., \ldots{} \& Moulder, J. E. (2007). Effect of an
  angiotensin II receptor blocker and two angiotensin converting enzyme
  inhibitors on transforming growth factor-\selectlanguage{greek}β \selectlanguage{english}(TGF-\selectlanguage{greek}β\selectlanguage{english}) and \selectlanguage{greek}α-\selectlanguage{english}Actomyosin (\selectlanguage{greek}α
  \selectlanguage{english}SMA), important mediators of radiation-induced pneumopathy and lung
  fibrosis. Current pharmaceutical design, 13(13), 1307-1316.
\item
  Monteil, V., Kwon, H., Prado, P., Hagelkr\selectlanguage{ngerman}üys, A., Wimmer, R. A.,
  Stahl, M., \ldots{} \& Romero, J. P. (2020). Inhibition of SARS-CoV-2
  infections in engineered human tissues using clinical-grade soluble
  human ACE2. Cell, DOI: 10.1016/j.cell.2020.04.004. Monteiro, R., \&
  Azevedo, I. (2010). Chronic inflammation in obesity and the metabolic
  syndrome. Mediators of inflammation, 2010.
\item
  Mortensen, E. M., Nakashima, B., Cornell, J., Copeland, L. A., Pugh,
  M. J., Anzueto, A., \ldots{} \& Fine, M. J. (2012). Population-based
  study of statins, angiotensin II receptor blockers, and
  angiotensin-converting enzyme inhibitors on pneumonia-related
  outcomes. Clinical infectious diseases, 55(11), 1466-1473.
\item
  Mortensen, E. M., Restrepo, M. I., Anzueto, A., \& Pugh, J. (2005).
  The impact of prior outpatient ACE inhibitor use on 30-day mortality
  for patients hospitalized with community-acquired pneumonia. BMC
  pulmonary medicine, 5(1), 12.
\item
  Mossel, E. C., Wang, J., Jeffers, S., Edeen, K. E., Wang, S.,
  Cosgrove, G. P., \ldots{} \& Holmes, K. V. (2008). SARS-CoV replicates
  in primary human alveolar type II cell cultures but not in type I-like
  cells. Virology, 372(1), 127-135.
\item
  Naicker, S., Yang, C. W., Hwang, S. J., Liu, B. C., Chen, J. H., \&
  Jha, V. (2020). The novel coronavirus 2019 epidemic and kidneys.
  Kidney International.
\item
  Noveanu, M., Breidthardt, T., Reichlin, T., Gayat, E., Potocki, M.,
  Pargger, H., \ldots{} \& Mebazaa, A. (2010). Effect of oral
  beta-blocker on short and long-term mortality in patients with acute
  respiratory failure: results from the BASEL-II-ICU study. Critical
  care, 14(6), R198.
\item
  Otsuka, M., Takahashi, H., Shiratori, M., Chiba, H., \& Abe, S.
  (2004). Reduction of bleomycin induced lung fibrosis by candesartan
  cilexetil, an angiotensin II type 1 receptor antagonist. Thorax,
  59(1), 31-38.
\item
  Oudit, G. Y., Kassiri, Z., Jiang, C., Liu, P. P., Poutanen, S. M.,
  Penninger, J. M., \& Butany, J. (2009). SARS\selectlanguage{english}-coronavirus modulation of
  myocardial ACE2 expression and inflammation in patients with SARS.
  European journal of clinical investigation, 39(7), 618-625.
\item
  Pan, F., Ye, T., Sun, P., Gui, S., Liang, B., Li, L., \ldots{} \&
  Zheng, C. (2020). Time course of lung changes on chest CT during
  recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology,
  200370.
\item
  Papp, M., Li, X., Zhuang, J., Wang, R., \& Uhal, B. D. (2002).
  Angiotensin receptor subtype AT1 mediates alveolar epithelial cell
  apoptosis in response to ANG II. American Journal of Physiology-Lung
  Cellular and Molecular Physiology, 282(4), L713-L718.
\item
  Parra, E. R., Ruppert, A. D. P., \& Capelozzi, V. L. (2014).
  Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate
  lung remodeling and fibrosis in systemic sclerosis and idiopathic
  pulmonary fibrosis. Clinics, 69(1), 47-54.
\item
  Patel, A. B., \& Verma, A. (2020). COVID-19 and Angiotensin-Converting
  Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the
  Evidence? JAMA. doi:10.1001/jama.2020.4812
\item
  Patel, V. B., Clarke, N., Wang, Z., Fan, D., Parajuli, N., Basu, R.,
  \ldots{} \& Oudit, G. Y. (2014). Angiotensin II induced proteolytic
  cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive
  feedback mechanism in the RAS. Journal of molecular and cellular
  cardiology, 66, 167-176.
\item
  Patel, V. B., Zhong, J. C., Grant, M. B., \& Oudit, G. Y. (2016). Role
  of the ACE2/angiotensin 1--7 axis of the renin--angiotensin system in
  heart failure. Circulation research, 118(8), 1313-1326.
\item
  Pedersen, S. F., \& Ho, Y. C. (2020). SARS-CoV-2: A Storm is Raging.
  The Journal of Clinical Investigation.
\item
  Phadke, M., \& Saunik, S. (2020). Rapid response: Use of angiotensin
  receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona
  Virus infections---Novel mode of treatment. Response to the emerging
  novel coronavirus outbreak. BMJ, 368, m406.
\item
  Pickel, L., Matsuzuka, T., Doi, C., Ayuzawa, R., Maurya, D. K., Xie,
  S. X., \ldots{} \& Tamura, M. (2010). Over-expression of angiotensin
  II type 2 receptor gene induces cell death in lung adenocarcinoma
  cells. Cancer biology \& therapy, 9(4), 277-285.
\item
  Pires-Neto, R. C., Morales, M. M. B., Lancas, T., Inforsato, N.,
  Duarte, M. I. S., Amato, M. B. P., \ldots{} \& Dolhnikoff, M. (2013).
  Expression of acute-phase cytokines, surfactant proteins, and
  epithelial apoptosis in small airways of human acute respiratory
  distress syndrome. Journal of critical care, 28(1), 111-e9.
\item
  Povlsen, A. L., Grimm, D., Wehland, M., Infanger, M., \& Kruger, M.
  (2020). The Vasoactive Mas Receptor in Essential Hypertension. Journal
  of Clinical Medicine, 9(1), 267.
\item
  Prompetchara, E., Ketloy, C., \& Palaga, T. (2020). Immune responses
  in COVID-19 and potential vaccines: Lessons learned from SARS and MERS
  epidemic. Asian Pac J Allergy Immunol, 38, 1-9.
\item
  Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., \ldots{} \&
  Tian, D. S. (2020). Dysregulation of immune response in patients with
  COVID-19 in Wuhan, China. China (February 17, 2020).
\item
  Reyes, S., Varagic, J., Ahmad, S., VonCannon, J., Kon, N. D., Wang,
  H., \ldots{} \& Ferrario, C. M. (2017). Novel cardiac intracrine
  mechanisms based on Ang-(1-12)/chymase axis require a revision of
  therapeutic approaches in human heart disease. Current hypertension
  reports, 19(2), 16.
\item
  Rodrigues-Diez, R., Carvajal-Gonzalez, G., Sanchez-Lopez, E.,
  Rodriguez-Vita, J., Diez, R. R., Selgas, R., \ldots{} \& Ruiz-Ortega,
  M. (2008). Pharmacological modulation of epithelial mesenchymal
  transition caused by angiotensin II. Role of ROCK and MAPK pathways.
  Pharmaceutical research, 25(10), 2447-2461.
\item
  Rothan, H. A., \& Byrareddy, S. N. (2020). The epidemiology and
  pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of
  Autoimmunity, 102433.
\item
  Rzepka, J. P., Haick, A. K., \& Miura, T. A. (2012). Virus-infected
  alveolar epithelial cells direct neutrophil chemotaxis and inhibit
  their apoptosis. American journal of respiratory cell and molecular
  biology, 46(6), 833-841.
\item
  Sakai, N., \& Tager, A. M. (2013). Fibrosis of two: Epithelial
  cell-fibroblast interactions in pulmonary fibrosis. Biochimica et
  Biophysica Acta (BBA)-Molecular Basis of Disease, 1832(7), 911-921.
\item
  Santos, R. A. (2014). Angiotensin-(1--7). Hypertension, 63(6),
  1138-1147.
\item
  Santos, R. A. S., Oudit, G. Y., Verano-Braga, T., Canta, G.,
  Steckelings, U. M., \& Bader, M. (2019). The renin-angiotensin system:
  going beyond the classical paradigms. American Journal of
  Physiology-Heart and Circulatory Physiology, 316(5), H958-H970.
\item
  Santos, R. A. S., Sampaio, W. O., Alzamora, A. C., Motta-Santos, D.,
  Alenina, N., Bader, M., \& Campagnole-Santos, M. J. (2018). The
  ACE2/angiotensin-(1--7)/MAS axis of the renin-angiotensin system:
  focus on angiotensin-(1--7). Physiological reviews, 98(1), 505-553.
\item
  Schmermund, A., Lerman, L. O., Ritman, E. L., \& Rumberger, J. A.
  (1999, May). Cardiac production of angiotensin II and its
  pharmacologic inhibition: effects on the coronary circulation. In Mayo
  Clinic Proceedings (Vol. 74, No. 5, pp. 503-513). Elsevier.
\item
  Shao, M., Wen, Z. B., Yang, H. H., Zhang, C. Y., Xiong, J. B., Guan,
  X. X., \ldots{} \& He, X. F. (2019). Exogenous angiotensin (1-7)
  directly inhibits epithelial-mesenchymal transformation induced by
  transforming growth factor-\selectlanguage{greek}β\selectlanguage{english}1 in alveolar epithelial cells.
  Biomedicine \& Pharmacotherapy, 117, 109193.
\item
  Shen, L., Mo, H., Cai, L., Kong, T., Zheng, W., Ye, J., \ldots{} \&
  Xiao, Z. (2009). losartan prevents sepsis-induced acute lung injury
  and decreases activation of nuclear factor\selectlanguage{greek}κ\selectlanguage{english}b and mitogen-activated
  protein kinases. Shock, 31(5), 500-506.
\item
  Shi, J., Wen, Z., Zhong, G., Yang, H., Wang, C., Huang, B., \ldots{}
  \& Zhao, Y. (2020). Susceptibility of ferrets, cats, dogs, and other
  domesticated animals to SARS--coronavirus 2. Science.
\item
  Shrikrishna, D., Astin, R., Kemp, P. R., \& Hopkinson, N. S. (2012).
  Renin--angiotensin system blockade: a novel therapeutic approach in
  chronic obstructive pulmonary disease. Clinical science, 123(8),
  487-498.
\item
  Singh, V. P., Baker, K. M., \& Kumar, R. (2008). Activation of the
  intracellular renin-angiotensin system in cardiac fibroblasts by high
  glucose: role in extracellular matrix production. American Journal of
  Physiology-Heart and Circulatory Physiology, 294(4), H1675-H1684.
\item
  Skov, J., Persson, F., Fr\selectlanguage{ngerman}økiær, J., \& Christiansen, J. S. (2014).
  Tissue renin--angiotensin systems: a unifying hypothesis of metabolic
  disease. Frontiers in endocrinology, 5, 23.
\item
  Sodhi, C. P., Nguyen, J., Yamaguchi, Y., Werts, A. D., Lu, P., Ladd,
  M. R., \ldots{} \& Zhang, Y. (2019). A Dynamic Variation of Pulmonary
  ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to
  Pseudomonas aeruginosa Lung Infection in Mice. The Journal of
  Immunology, 203(11), 3000-3012.
\item
  Sriram, K., \& Insel, P. A. (2020). Dangers of ACE inhibitor and ARB
  usage in COVID-19: evaluating the evidence. medRxiv.
\item
  Stebbing, J., Phelan, A., Griffin, I., Tucker, C., Oechsle, O., Smith,
  D., \& Richardson, P. (2020). COVID-19: combining antiviral and
  anti-inflammatory treatments. The Lancet Infectious Diseases.
\item
  Suk, J. S., \& Ensign-Hodges, L. (2019). Development of Angiotensin II
  Receptor Blocker Nanoparticles for an Inhaled Therapeutic Treatment of
  COPD via TGF-Beta Antagonism (Doctoral dissertation, Johns Hopkins
  University).
\item
  Sun, P., Lu, X., Xu, C., Sun, W., \& Pan, B. (2020). Understanding of
  COVID\selectlanguage{english}-19 based on current evidence. Journal of medical virology.
\item
  Sutton, T. C., \& Subbarao, K. (2015). Development of animal models
  against emerging coronaviruses: From SARS to MERS coronavirus.
  Virology, 479, 247-258.
\item
  Thevarajan, I., Nguyen, T. H., Koutsakos, M., Druce, J., Caly, L., van
  de Sandt, C. E., \ldots{} \& Tong, S. Y. (2020). Breadth of
  concomitant immune responses prior to patient recovery: a case report
  of non-severe COVID-19. Nature Medicine, 1-3.
\item
  Tian, S., Hu, W., Niu, L., Liu, H., Xu, H., \& Xiao, S. Y. (2020).
  Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19)
  pneumonia in two patients with lung cancer. Journal of Thoracic
  Oncology.
\item
  Tikellis, C., \& Thomas, M. C. (2012). Angiotensin-converting enzyme 2
  (ACE2) is a key modulator of the renin angiotensin system in health
  and disease. International journal of peptides, 2012.
\item
  To, K. K. W., Tsang, O. T. Y., Leung, W. S., Tam, A. R., Wu, T. C.,
  Lung, D. C., \ldots{} \& Lau, D. P. L. (2020). Temporal profiles of
  viral load in posterior oropharyngeal saliva samples and serum
  antibody responses during infection by SARS-CoV-2: an observational
  cohort study. The Lancet Infectious Diseases.
\item
  Uhal, B. D., Dang, M. T. T., Li, X., \& Abdul-Hafez, A. (2012).
  Angiotensinogen gene transcription in pulmonary fibrosis.
  International journal of peptides, 2012.
\item
  Uhal, B. D., Kyong Kim, J., Li, X., \& Molina-Molina, M. (2007).
  Angiotensin-TGF-\selectlanguage{greek}β\selectlanguage{english}1 crosstalk in human idiopathic pulmonary fibrosis:
  autocrine mechanisms in myofibroblasts and macrophages. Current
  pharmaceutical design, 13(12), 1247-1256.
\item
  Uhal, B. D., Li, X., Piasecki, C. C., \& Molina-Molina, M. (2012b).
  Angiotensin signalling in pulmonary fibrosis. The international
  journal of biochemistry \& cell biology, 44(3), 465-468.
\item
  Uhal, B. D., Li, X., Xue, A., Gao, X., \& Abdul-Hafez, A. (2011).
  Regulation of alveolar epithelial cell survival by the
  ACE-2/angiotensin 1--7/Mas axis. American Journal of Physiology-Lung
  Cellular and Molecular Physiology, 301(3), L269-L274.
\item
  Uhal, B. D., Nguyen, H., Dang, M., Gopallawa, I., Jiang, J., Dang, V.,
  \ldots{} \& Morimoto, K. (2013). Abrogation of ER stress-induced
  apoptosis of alveolar epithelial cells by angiotensin 1--7. American
  Journal of Physiology-Lung Cellular and Molecular Physiology, 305(1),
  L33-L41.
\item
  Vaduganathan, M., Vardeny, O., Michel, T., McMurray, J. J., Pfeffer,
  M. A., \& Solomon, S. D. (2020). Renin--Angiotensin--Aldosterone
  System Inhibitors in Patients with Covid-19. New England Journal of
  Medicine. doi: 10.1056/NEJMsr2005760
\item
  van de Garde, E. M., Souverein, P. C., Hak, E., Deneer, V. H., van den
  Bosch, J. M., \& Leufkens, H. G. (2007). Angiotensin-converting enzyme
  inhibitor use and protection against pneumonia in patients with
  diabetes. Journal of hypertension, 25(1), 235-239.
\item
  Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T.,
  \& Veesler, D. (2020). Structure, function, and antigenicity of the
  SARS-CoV-2 spike glycoprotein. Cell.
\item
  Wan, Y., Shang, J., Graham, R., Baric, R. S., \& Li, F. (2020).
  Receptor recognition by the novel coronavirus from Wuhan: an analysis
  based on decade-long structural studies of SARS coronavirus. Journal
  of virology, 94(7).
\item
  Wang, D., Chai, X. Q., Magnnusen, C. G., Zosky, G. R., Shu, S. H.,
  Wei, X., \& Hu, S. S. (2019). Renin-angiotensin-system, a potential
  pharmacological candidate, in acute respiratory distress syndrome
  during mechanical ventilation. Pulmonary pharmacology \& therapeutics,
  101833.
\item
  Wang, L., Wang, Y., Yang, T., Guo, Y., \& Sun, T. (2015).
  Angiotensin-converting enzyme 2 attenuates bleomycin-induced lung
  fibrosis in mice. Cellular Physiology and Biochemistry, 36(2),
  697-711.
\item
  Wang, R., Alam, G., Zagariya, A., Gidea, C., Pinillos, H., Lalude, O.,
  \ldots{} \& Uhal, B. D. (2000). Apoptosis of lung epithelial cells in
  response to TNF-\selectlanguage{greek}α \selectlanguage{english}requires angiotensin II generation de novo. Journal
  of cellular physiology, 185(2), 253-259.
\item
  Wang, R., Ramos, C., Joshi, I., Zagariya, A., Pardo, A., Selman, M.,
  \& Uhal, B. D. (1999a). Human lung myofibroblast-derived inducers of
  alveolar epithelial apoptosis identified as angiotensin peptides.
  American Journal of Physiology-Lung Cellular and Molecular Physiology,
  277(6), L1158-L1164.
\item
  Wang, R., Zagariya, A., Ang, E., Ibarra-Sunga, O., \& Uhal, B. D.
  (1999b). Fas-induced apoptosis of alveolar epithelial cells requires
  ANG II generation and receptor interaction. American Journal of
  Physiology-Lung Cellular and Molecular Physiology, 277(6),
  L1245-L1250.
\item
  Wang, R., Zagariya, A., Ibarra-Sunga, O., Gidea, C., Ang, E.,
  Deshmukh, S., \ldots{} \& Uhal, B. D. (1999c). Angiotensin II induces
  apoptosis in human and rat alveolar epithelial cells. American Journal
  of Physiology-Lung Cellular and Molecular Physiology, 276(5),
  L885-L889.
\item
  Waseda, Y., Yasui, M., Nishizawa, Y., Inuzuka, K., Takato, H.,
  Ichikawa, Y., \ldots{} \& Nakao, S. (2008). Angiotensin II type 2
  receptor antagonist reduces bleomycin-induced pulmonary fibrosis in
  mice. Respiratory research, 9(1), 43.
\item
  Watanabe, T., Barker, T. A., \& Berk, B. C. (2005). Angiotensin II and
  the endothelium: diverse signals and effects. Hypertension, 45(2),
  163-169.
\item
  Wen, H., Gwathmey, J. K., \& Xie, L. H. (2012). Oxidative
  stress-mediated effects of angiotensin II in the cardiovascular
  system. World journal of hypertension, 2(4), 34.
\item
  Wong, S. K., Li, W., Moore, M. J., Choe, H., \& Farzan, M. (2004). A
  193-amino acid fragment of the SARS coronavirus S protein efficiently
  binds angiotensin-converting enzyme 2. Journal of Biological
  Chemistry, 279(5), 3197-3201.
\item
  W\selectlanguage{ngerman}östen-van Asperen, R. M., Lutter, R., Haitsma, J. J., Merkus, M. P.,
  van Woensel, J. B., Van Der Loos, C. M., \ldots{} \& Bos, A. P.
  (2008). ACE mediates ventilator-induced lung injury in rats via
  angiotensin II but not bradykinin. European Respiratory Journal,
  31(2), 363-371.
\item
  Wösten\selectlanguage{english}-van Asperen, R. M., Lutter, R., Specht, P. A., Moll, G. N., van
  Woensel, J. B., van der Loos, C. M., \ldots{} \& Bos, A. P. (2011).
  Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2
  activities and is prevented by angiotensin\selectlanguage{english}-(1--7) or an angiotensin II
  receptor antagonist. The Journal of pathology, 225(4), 618-627.
\item
  Wright, J. R. (2003). Pulmonary surfactant: a front line of lung host
  defense. The Journal of clinical investigation, 111(10), 1453-1455.
\item
  Wu, H., Li, Y., Wang, Y., Xu, D., Li, C., Liu, M., \ldots{} \& Li, Z.
  (2014). Tanshinone IIA attenuates bleomycin-induced pulmonary fibrosis
  via modulating angiotensin-converting enzyme 2/angiotensin-(1-7) axis
  in rats. International journal of medical sciences, 11(6), 578.
\item
  Wu, Z., \& McGoogan, J. M. (2020). Characteristics of and important
  lessons from the coronavirus disease 2019 (COVID-19) outbreak in
  China: summary of a report of 72 314 cases from the Chinese Center for
  Disease Control and Prevention. Jama.
\item
  Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., \ldots{} \&
  Chen, Q. (2020a). High expression of ACE2 receptor of 2019-nCoV on the
  epithelial cells of oral mucosa. International Journal of Oral
  Science, 12(1), 1-5.
\item
  Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., \ldots{}
  \& Tai, Y. (2020b). Pathological findings of COVID-19 associated with
  acute respiratory distress syndrome. The Lancet respiratory medicine.
\item
  Yan, Y., Liu, Q., Li, N., Du, J., Li, X., Li, C., \ldots{} \& Jiang,
  C. (2015). Angiotensin II receptor blocker as a novel therapy in acute
  lung injury induced by avian influenza A H5N1 virus infection in
  mouse. Science China Life Sciences, 58(2), 208-211.
\item
  Yao, H. W., Zhu, J. P., Zhao, M. H., \& Lu, Y. (2006). Losartan
  attenuates bleomycin-induced pulmonary fibrosis in rats. Respiration,
  73(2), 236-242.
\item
  Yasui, F., Kohara, M., Kitabatake, M., Nishiwaki, T., Fujii, H.,
  Tateno, C., \ldots{} \& Kai, C. (2014). Phagocytic cells contribute to
  the antibody-mediated elimination of pulmonary-infected SARS
  coronavirus. Virology, 454, 157-168.
\item
  Zhang, H., Penninger, J. M., Li, Y., Zhong, N., \& Slutsky, A. S.
  (2020). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2
  receptor: molecular mechanisms and potential therapeutic target.
  Intensive Care Medicine, 1-5.
\item
  Zhang, Y., Li, Y., Shi, C., Fu, X., Zhao, L., \& Song, Y. (2018).
  Angiotensin\selectlanguage{english}-(1\selectlanguage{english}-7)\selectlanguage{english}-mediated Mas1 receptor/NF\selectlanguage{english}-\selectlanguage{greek}κ\selectlanguage{english}B-p65 signaling is
  involved in a cigarette smoke-induced chronic obstructive pulmonary
  disease mouse model. Environmental toxicology, 33(1), 5-15.
\item
  Zhao, J., Zhao, J., Van Rooijen, N., \& Perlman, S. (2009). Evasion by
  stealth: inefficient immune activation underlies poor T cell response
  and severe disease in SARS-CoV-infected mice. PLoS pathogens, 5(10).
\item
  Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., \ldots{} \& Guan,
  L. (2020a). Clinical course and risk factors for mortality of adult
  inpatients with COVID-19 in Wuhan, China: a retrospective cohort
  study. The Lancet. 395( 10229), P1054-1062
\item
  Zhou, J. B., Yang, J. K., Lu, J. K., \& An, Y. H. (2010).
  Angiotensin-converting enzyme gene polymorphism is associated with
  type 2 diabetes: a meta-analysis. Molecular biology reports, 37(1),
  67-73.
\item
  Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W.,
  \ldots{} \& Chen, H. D. (2020b). A pneumonia outbreak associated with
  a new coronavirus of probable bat origin. Nature, 579(7798), 270-273.
\item
  Zou, X., Chen, K., Zou, J., Han, P., Hao, J., \& Han, Z. (2020).
  Single-cell RNA-seq data analysis on the receptor ACE2 expression
  reveals the potential risk of different human organs vulnerable to
  2019-nCoV infection. Frontiers of Medicine, 1-8.
\end{enumerate}

\emph{Figure Legends}

\textbf{Figure 1. A schema identifying the tissues impacted by
SARS-CoV-2 infection and COVID-19 pathobiology} . Dashed arrows identify
events whose role is as-yet unclear

\textbf{Figure 2. Renin-Angiotensin signaling (RAS), Angiotensin (ANG
II) signaling, the balance between ACE1 and ACE2, and in red, the impact
of COVID-19.} APs: Aminopeptidases; PREP: prolyl endopeptidase; MME:
membrane metalloendopeptidase.

\textbf{Figure 3} . Hypothesized model of cell-cell communication and
pathobiology in pulmonary infection from SARS-CoV-2 and the role of
ACE1- and ACE2-derived peptides in mediating these effects on several
different cell types.

\textbf{Figure 4. ACE1/ACE2 imbalance, lung injury, and factors that
determine severe pathology or mild illness. (A.)} A model for the course
of COVID-19 that links ACE1/ACE2 imbalance to lung injury via the RAS
pathway and the protective role of the immune response. \textbf{(B.)} An
illustration of the predicted course of COVID-19 in two
settings:\textbf{top} : Severe pathology, in patients who lack
appropriate immune response or who have prior conditions that enhance
ACE1/ACE imbalance (and RAS-induced injury). The result is increased
injury that overwhelms the adaptive immune response; \textbf{bottom} :
Mild illness, in which patients lack underlying conditions and can mount
an appropriate immune response, so that RAS-induced injury is less
serious, an effective immune response occurs and the infection is
resolved.

\textbf{Figure 5} . \textbf{Hypothesized model of cell-cell
communication in myocardial infection from SARS-CoV-2 and the influence
of ACE1/ACE2 imbalance on a variety of cell types involved in cardiac
injury.}

\textbf{Figure 6.} \textbf{Pharmacological agents that target the RAS
pathway and counteract effects of SARS-CoV-2 infection.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2/Figure2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure3/Figure3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure4a/Figure4a}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure4b/Figure4b}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure5/Figure5}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure6/Figure6}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

