The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.
Isabella Z MoreiraAntônio Felipe Silva CarvalhoLaís C GrossiJéssica A M SouzaEdvaldo S LaraAna Clara M Montuori-AndradeCamila CardosoFernanda S CarneiroErick Bryan de Sousa LimaAdelson Héric Alves MonteiroIsabella de Lacerda AugustoRodrigo Severo CaixetaCarlos Eduardo Dias IgídioCamila Bernardo de BritoLeonardo Camilo de OliveiraCelso Martins Queiroz-JuniorRemo Castro RussoMaria José Campagnole-SantosRobson Augusto Souza Dos SantosVivian Vasconcelos CostaDanielle da Glória SouzaCaio Tavares FagundesMauro Martins TexeiraLuciana Pádua TavaresLirlândia Pires SousaPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2024)
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.
Keyphrases
- angiotensin ii
- pseudomonas aeruginosa
- oxidative stress
- cystic fibrosis
- angiotensin converting enzyme
- community acquired pneumonia
- respiratory failure
- anti inflammatory
- staphylococcus aureus
- acinetobacter baumannii
- big data
- early onset
- type diabetes
- emergency department
- intensive care unit
- gene expression
- escherichia coli
- genome wide
- risk assessment
- machine learning
- social support
- metabolic syndrome
- cell therapy
- mesenchymal stem cells
- binding protein
- candida albicans
- high resolution
- acute respiratory distress syndrome
- dna methylation
- data analysis
- extracorporeal membrane oxygenation
- artificial intelligence