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‐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-β1 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-β1-induced EMT and activation of targets downstream of TGF-β1 (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 (Magalhães 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.