Avaliação do papel da Angiotensina-(1-7) e do seu receptor Mas em modelos pré-clínicos de doenças infecciosas.

Abstract

Infectious diseases represent one of the leading causes of death worldwide. The limited availability of antimicrobial therapies and increased resistance to existing drugs make the therapeutic management of infectious diseases a challenge. Inflammation is a primordial physiological response aimed to protect the host against invading microorganisms and must be balanced and self-limited to ensure pathogen clearance and tissue homeostasis. However, overwhelming, or dysfunctional inflammation is a determinant factor for severity and mortality during infections. In recent years, emerging studies have highlighted the role of inflammation resolution on modulating host responses to ensure pathogen control and inflammatory responses during infections. Inflammation resolution is an active and integrated process that is coordinated by different pro-resolving mediators, including Angiotensin-(1-7) [Ang-(1-7)] - an endogenous bioactive peptide that takes part of the counter-regulatory axis of the renin-angiotensin system (RAS). The actions of Ang-(1-7) occur mainly through its binding to the Mas receptor (MasR), a G protein-coupled receptor. Among its anti-inflammatory actions, Ang-(1-7) acting via MasR, reduces the recruitment of leukocytes, especially granulocytes, and prevents tissue damage related to the overactivation of inflammation, such as fibrosis. The present work highlights the importance of the Ang-(1-7)/Mas axis in two different infectious models: peritonitis induced by Escherichia coli and pneumonia caused by Pseudomonas aeruginosa. In the peritonitis model, the absence of the Mas receptor resulted in a delay on resolution of inflammation, by compromising the recruitment of macrophages to the peritoneal cavity, reducing the efferocytosis of apoptotic neutrophils and bacterial clearance. Similarly, during P. aeruginosa-induced pneumonia, Mas receptor-deficient mice also developed a more severe form of pneumonia, with higher numbers of neutrophils in the BAL, increased bacterial load, and higher levels of cytokines and chemokines as compared to WT mice. Histopathological analyzes of the lungs show severe pulmonary damage after P. aeruginosa infection, which were similar in both genotypes. Interestingly, treatment with Ang- (1-7) during P. aeruginosa infection was able to decrease neutrophilic infiltration alongside decreased levels of pro-inflammatory cytokines and chemokines in BAL, lung and plasma of infected animals. Moreover, the peptide was able to decrease the bacterial load and reduces the P. aeruginosa-elicited lung damage. The identification of pro-resolving and anti-inflammatory mechanisms of Ang-(1- 7) will pave the way for the development of host-directed therapies in order to promote mechanisms of resistance and resilience to infections.