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.