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. γ-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 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, Wösten-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.