Angiotensin-(1–7) Promotes Resolution of Eosinophilic Inflammation in an Experimental Model of Asthma

Abstract

Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1–7) [Ang-(1–7)], a pivotal peptide of the renin–angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1–7) at the peak of the inflammatory process. Bronchoalveolar lavage (BAL) fluid and lungs were collected 24 h after treatment. Different lung lobes were processed for histology to evaluate inflammatory cell infiltration, airway and pulmonary remodeling, total collagen staining, and measurements of (i) collagen I and III mRNA expression by qRT-PCR; (ii) ERK1/2, IκB-α, and GATA3 protein levels by Western blotting; and (iii) eosinophilic peroxidase activity. Total number of inflammatory cells, proportion of apoptotic eosinophils and immunofluorescence for caspase 3 and NF-κB in leukocytes were evaluated in the BAL. Mas receptor immunostaining was evaluated in mouse and human eosinophils. Engulfment of human polimorphonuclear cells by macrophages, efferocytosis, was evaluated in vivo. Ang-(1–7) reduced eosinophils in the lung and in the BAL, increased the number of apoptotic eosinophils, shown by histology criteria and by increase in caspase 3 immunostaining. Furthermore, Ang-(1–7) decreased NF-kB immunostaining in eosinophils, reduced GATA3, ERK1/2, and IκB-α expression in the lung and decreased pulmonary remodeling and collagen deposition. Importantly, Ang-(1–7) increased efferocytosis. Our results demonstrate, for the first time, Ang-(1–7) activates events that are crucial for resolution of the inflammatory process of asthma and promotion of the return of lung homeostasis, indicating Ang-(1–7) as novel endogenous inflammation-resolving mediator.

Counter-regulatory renin–angiotensin system in cardiovascular disease

“…Moreover, long term angiotensin 1-7 treatment confers both vasoprotection (by improving endothelial function) and atheroprotection (by reducing lesion progression) in Apoe −/− mice 115 . Consistent with these observations, angiotensin 1-7 can activate signal ling pathways critical for the resolution of inflammatory processes involved in asthma 116 .…”

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…Ang‐(1‐7) has been shown to have anti‐inflammatory and proresolutive effects in murine models of arthritis and asthma . Due to this, we wondered if the oral treatment with Ang‐(1‐7) would decrease inflammation and collagen deposition in a model of pulmonary fibrosis induced by BLM.…”

“…Ang-(1-7) has been shown to have anti-inflammatory and proresolutive effects in murine models of arthritis and asthma. 16,17 Neutrophils are thought to play an important role in the activation of fibrogenesis. 23 Here, we showed that the preventive treatment with Ang-(1-7) caused reduction in the number of neutrophils and mononuclear cells in the lungs of mice given BLM.…”

“…Previous experiments have shown that Ang‐(1‐7) did not affect baseline parameters in the lung . The dose of Ang‐(1‐7) chosen was shown to cause significant decrease in various parameters in other models of inflammation . The weight of animals was evaluated on every 3 days and any death daily.…”

Yin-Yang Balance of ACE/ACE2 Pathways: The Rational for ACE2 Pathway Inhibitor Administration in SARS-CoV-2 Patients

“…Moreover, Ang-(1-7) alone either activated the bax/caspasedependent apoptotic pathway or upregulated NF-kB signaling in lung fibroblasts in vitro 14 . To this regard, Ang-(1-7) has been also reported to promote eosinophil apoptosis in the lung and in the broncoalveolar lavage 8 . Interestingly, Ang-(1-7)/Mas receptor axis inhibits allergic airway inflammation and eosinophil cell counts in a murine model of asthma, indicating that both an impairment of ACE2 pathway may favor asthma and ACE2 pathway activation can reduces asthma symptoms 14 .…”