The Anti-Inflammatory and Proresolving Mediator Resolvin E1 Protects Mice from Bacterial Pneumonia and Acute Lung Injury

Abstract

Whereas pneumonia is the most common cause of death and disability worldwide, most cases of pneumonia spontaneously resolve. Mechanisms that promote pneumonia resolution remain to be determined. Resolvin E1 (RvE1) is an endogenous mediator that displays proresolving actions in sterile inflammation. In this study, we developed a new model of aspiration pneumonia to evaluate the effect of RvE1 on acute lung injury caused by acid aspiration and subsequent bacterial challenge. Mice received hydrochloric acid into the left lung followed by the enteric pathogen Escherichia coli. I.v. administration of RvE1 (∼0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several proinflammatory chemokines and cytokines, including IL-1β, IL-6, HMGB-1, MIP-1α, MIP-1β, keratinocyte-derived chemokine, and MCP-1, in a manner independent of the anti-inflammatory mediators IL-10 and lipoxin A4. In addition, animals treated with RvE1 had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents the first candidate for a novel therapeutic strategy for acute lung injury and pneumonia that harnesses natural resolution mechanisms.

Resolvin D1 Reduces Emphysema and Chronic Inflammation

“…49 RvD1 also directly inhibits neutrophil chemotaxis. 21,50 Here, we found that AT-RvD1 dramatically altered the inflammatory environment in cigarette smokeeexposed lungs, with reductions in total inflammatory cells, neutrophils, and the expression of proinflammatory cytokines, Cox-2, and ICAM-1, and increased expression of IL-10. We hypothesize that the reduction in inflammation results from both the direct inhibition of neutrophil chemotaxis and activation as well as inhibition of proinflammatory signaling by epithelial and other lung cells, resulting in decreased levels of expression of chemotactic factors and adhesion molecules.…”

“…We and others have reported that RvD1 promotes alternative activation of macrophages (the M2 phenotype) 11,50 and that the M2 macrophages appear to mitigate inflammation and promote the resolution of inflammation in acute models and cell culture systems. 11,51 However, some evidence suggests that in chronic diseases, M2 macrophages may promote tissue remodeling and repair, leading to fibrosis.…”

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

“…19 A total of 1 Â 10 6 colony-forming units of Escherichia coli were introduced to the left mainstem bronchus (total volume, 25 mL). Mice were given ATRvD3 (10 ng, i.v.)…”

Papel dos ácidos graxos ômega 3 na resolução dos processos inflamatórios

“…RvE1 diminui a expressão de CD18 em Neutrófilos e Monócitos e modifica a ação da Lselectina (que está relacionada aos eventos iniciais do recrutamento de Leucócitos), resultando na redução da migração de Neutrófilos para o local da inflamação. 2,[54][55][56][57] As resolvinas são produzidas em resposta a um estímulo, têm ação local e têm metabolização por vias enzimáticas que levam à sua inativação. As RvE1 podem ser convertidas a diferentes metabólitos (20-hidroxi-RvE1, 20-carboxi-RvE1, 19-hidroxi-ReV1, 18-oxo-RvE1 e 10, 11-diidro-RvE1) em Neutrófilos humanos que são biologicamente inativos se comparados às RvE1.…”

“…As RvE1 podem ser convertidas a diferentes metabólitos (20-hidroxi-RvE1, 20-carboxi-RvE1, 19-hidroxi-ReV1, 18-oxo-RvE1 e 10, 11-diidro-RvE1) em Neutrófilos humanos que são biologicamente inativos se comparados às RvE1. 2,48,[55][56][57] …”