The angiotensin‐(1‐7)/ <scp>MasR</scp> axis improves pneumonia caused by <i>Pseudomonas aeruginosa</i> : 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.
Authors
- Remo Castro Russo (ORCID: https://orcid.org/0000-0002-1715-3834)
- Luciana P. Tavares (ORCID: https://orcid.org/0000-0002-5319-0210)
- Isabella Zaidan (ORCID: https://orcid.org/0000-0001-9434-8814)
- Lirlândia P. Sousa (ORCID: https://orcid.org/0000-0002-1042-9762)
- Celso Martins Queiroz‐Junior (ORCID: https://orcid.org/0000-0002-7884-7709)
- Mauro Martins Teixeira (ORCID: https://orcid.org/0000-0002-6944-3008)
- Danielle G. Souza (ORCID: https://orcid.org/0000-0002-7478-5934)
- A. Monteiro (ORCID: https://orcid.org/0009-0001-8334-1219)
- Érick Bryan de Sousa Lima (ORCID: https://orcid.org/0000-0003-2052-2976)
- Caio T. Fagundes (ORCID: https://orcid.org/0000-0002-6747-5233)
- Leonardo Camilo de Oliveira (ORCID: https://orcid.org/0000-0002-7393-5013)
- Camila Cardoso (ORCID: https://orcid.org/0000-0001-8131-579X)
- Fernanda S. Carneiro (ORCID: https://orcid.org/0000-0002-5776-1519)
- Antônio Felipe Silva Carvalho (ORCID: https://orcid.org/0000-0001-6185-274X)
- Ana Clara M. Montuori‐Andrade (ORCID: https://orcid.org/0000-0002-1864-4838)
- Camila Bernardo de Brito (ORCID: https://orcid.org/0000-0002-4571-7238)
- Jéssica Amanda Marques Souza
- Vivian Vasconcelos Costa (ORCID: https://orcid.org/0000-0002-0175-642X)
- Laís C. Grossi
- Maria José Campagnole‐Santos (ORCID: https://orcid.org/0000-0001-9483-4206)
- Robson A.S. Santos (ORCID: https://orcid.org/0000-0001-8738-5852)
- Carlos Eduardo Dias Igídio (ORCID: https://orcid.org/0000-0002-7480-5405)
- Isabella de Lacerda Augusto
- Rodrigo Severo Caixeta
- Edvaldo S. Lara
Institutions
- Universidade Federal de Minas Gerais (BR)
- Brigham and Women's Hospital (US)
- Hospital de Clínicas de Porto Alegre (BR)
- Hospital das Clínicas da Universidade Federal de Minas Gerais (BR)
Publication Details
- Journal
- The FASEB Journal
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1096/fj.202401178r
- Citations
- 4
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 1.07
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais