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).
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 (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-Díez
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-β, IL-6, IL-8, MCP-1 and TNF-α) (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
(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).