Protective role of ACE Inhibitor and ARBs.
ACE2 negatively regulates RAS and counterbalances the effect of ACE.
From the previous study, it is known that compared to other classes of
antihypertensive drugs, treatment with ACE inhibitors or ARBs leads to
significant increase in CD8+ T cell counts in peripheral blood.
Additionally, during hospitalization the peak viral load is
significantly lower compared to non-ACEI/ARB-treated group (Zhang et
al., 2020). Also, both ACEI and ARBs have shown to reduce inflammation
by upregulating TGF-β as well as by increasing regulatory T cells
(Sepheri et al., 2016; Platten et al., 2009). Previous biological
findings have also shown that ACE inhibitors play anti-inflammatory
effect by reducing mRNA expression of multiple pro-inflammatory
cytokines such as IL-1β, IL-6, IL-8, TNF-α, interferon, and MCP-1, as
well as aortic wall IL-8 and MCP-1, thereby reducing vascular
inflammation (Kim et al., 2014). ACE inhibitor viz. captopril plays a
protective role by reducing the expression of intercellular adhesion
molecule-1 in the lung tissue and in the circulating endothelial cells
in the blood, block the NF-kB activation and recovery of the
fibrinolytic disturbance in lung tissue (He et al., 2007). ARBs viz.
losartan treatment has shown significant reduction in pro-inflammatory
cytokine (TNF-α, IL-6, and IL-1β production) and improves lung injury
(Shen et al., 2009; Li et al., 2015b). Retrospective studies in humans
showed that ACEIs/ARBs can reduce the severity of pneumonia (Caldeira et
al., 2012; Mortensen et al., 2012). As ACEIs partially block the
formation of ANG II, the low level of ANG II has a favorable effect due
to low level of proinflammatory cytokines. In turn, pathway A becomes
predominant causing increased activity of ACE2 generating Ang (1-9),
which ameliorates pulmonary hypertension, improves pulmonary vascular
remodeling and has an anti-inflammatory effect (Figure 1, Pathway A)
(Cha et al., 2018; Li et al., 2017). Ang(1-9) also plays a protective
role by inhibiting infiltration of inflammatory cells and decreasing the
level of cytokines in plasma via AT2R receptor, which in turn induces
protein tyrosine phosphatase (PTP), IkB (NF-kB inhibitor) and ATF2
transcription factor phosphorylation, as well as JNK, p38MAPK, ERK1/2,
and STAT3 dephosphorylation, all of which have roles in ameliorating
pulmonary, cardiovascular and renal inflammation (Cha et al., 2018;
Gonzalez et al., 2018).
Other than blocking AT1R, the major protective mechanisms of ARBs also
include reduction in pulmonary edema and vascular permeability. ARBs can
cause downregulation of proinflammatory cytokines and NFκB pathway with
reduction of pro-inflammatory cytokines, chemokines and reactive oxygen
species (Saavedra et al., 2020). ARBs can prevent binding of ANG II to
the AT1R, thus escalating ACE2 activity; which in turn produces Ang(1-7)
and counterbalances the inflammatory activity of ANG II. (Figure 1,
Pathway B). Ang (1-7) also has effects, similar to Ang (1-9), in
protecting against the inflammatory response mediated by Mas receptor
axis in various disease including asthma, pancreatic disease,
cardiovascular disease (Santuchi et al., 2019; Yu et al., 2018;
Magalhaes et al., 2018; Rodrigues et al., 2017) .Particularly some
evidences proved that Ang (1-7) has anti-inflammatory role in mitigating
pulmonary disease. Meng et al. reported that ACE-2/angiotensin-(1-7)/Mas
axis protects against bleomycin (BLM)-induced pulmonary fibrosis via
inhibition of MAP kinase and NF-kB pathway (Meng et al., 2014). Wu et
al. also reported protective role by ACE2/ANG (1-7) in bleomycin treated
rats (Wu et al., 2014). In a COPD murine model Zhang et al. showed
Ang(1-7) protects against pulmonary inflammation and fibrosis (Zhang et
al., 2018). Treatment with ARB viz losartan or Ang (1-7) reduced lung
inflammation and improved lung function in LPS induced Acute respiratory
distress syndrome (ARDS) models in rats (Wösten-van Asperen et al.,
2011).It is evident that there are cross-talks between the receptor and
peptides which in combination give an anti-inflammatory response and
drive vascular remodeling in pulmonary disease.