Relevance of angiotensin-(1-7) and its receptor Mas in pneumonia caused by influenza virus and post-influenza pneumococcal infection.

Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated with secondary pneumococcal infection. Therapeutic strategies based on pro-resolving molecules have great potential against acute inflammatory diseases. Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator that acts on its Mas receptor (MasR) to promote resolution of inflammation. We investigated the effects of Ang-(1-7) and the role of MasR in the context of primary IAV infection and secondary pneumococcal infection and evaluated pulmonary inflammation, virus titers and bacteria counts, and pulmonary damage. Therapeutic treatment with Ang-(1-7) decreased neutrophil recruitment, lung injury, viral load and morbidity after a primary IAV infection. Ang-(1-7) induced apoptosis of neutrophils and efferocytosis of these cells by alveolar macrophages, but had no direct effect on IAV replication in vitro. MasR-deficient (MasR-/-) mice were highly susceptible to IAV infection, displaying uncontrolled inflammation, increased viral load and greater lethality rate, as compared to WT animals. Ang-(1-7) was not protective in MasR-/- mice. Interestingly, Ang-(1-7) given during a sublethal dose of IAV infection greatly reduced morbidity associated with a subsequent S. pneumoniae infection, as seen by decrease in the magnitude of neutrophil influx, number of bacteria in the blood leading to a lower lethality. Altogether, these results show that Ang-(1-7) is highly protective against severe primary IAV infection and protects against secondary bacterial infection of the lung. These effects are MasR-dependent. Mediators of resolution of inflammation, such as Ang-(1-7), should be considered for the treatment of pulmonary viral infections.

Melo EM ，Del Sarto J ，Vago JP ，Tavares LP ，Rago F ，Gonçalves APF ，Machado MG ，Aranda-Pardos I ，Valiate BVS ，Cassali GD ，Pinho V ，Sousa LP ，A-Gonzalez N ，Campagnole-Santos MJ ，Bader M ，Santos RAS ，Machado AV ，Ludwig S ，Teixeira MM ... -  《-》

The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.

Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.

Zaidan I ，Carvalho AFS ，Grossi LC ，Souza JAM ，Lara ES ，Montuori-Andrade ACM ，Cardoso C ，Carneiro FS ，Lima EBS ，Monteiro AHA ，Augusto IL ，Caixeta RS ，Igídio CED ，de Brito CB ，de Oliveira LC ，Queiroz-Junior CM ，Russo RC ，Campagnole-Santos MJ ，Santos RAS ，Costa VV ，de Souza DDG ，Fagundes CT ，Teixeira MM ，Tavares LP ，Sousa LP ... -  《-》

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis.

Zaidan I ，Tavares LP ，Sugimoto MA ，Lima KM ，Negreiros-Lima GL ，Teixeira LC ，Miranda TC ，Valiate BV ，Cramer A ，Vago JP ，Campolina-Silva GH ，Souza JA ，Grossi LC ，Pinho V ，Campagnole-Santos MJ ，Santos RA ，Teixeira MM ，Galvão I ，Sousa LP ... -  《JCI Insight》

Single-walled carbon nanotubes modulate pulmonary immune responses and increase pandemic influenza a virus titers in mice.

Chen H ，Zheng X ，Nicholas J ，Humes ST ，Loeb JC ，Robinson SE ，Bisesi JH Jr ，Das D ，Saleh NB ，Castleman WL ，Lednicky JA ，Sabo-Attwood T ... -  《Virology Journal》

Cysteinyl Maresins Reprogram Macrophages to Protect Mice from Streptococcus pneumoniae after Influenza A Virus Infection.

P Tavares L ，Brüggemann TR ，M Rezende R ，G Machado M ，Cagnina RE ，Shay AE ，C Garcia C ，Nijmeh J ，M Teixeira M ，Levy BD ... -  《mBio》