Specialized pro-resolving mediators MaR1 and LXA4 resolve inflammation during acute chemical lung injury in the absence of neutrophils.

Gastric aspiration pneumonia involves chemical injury to the alveoli of the lungs with inflammation, tissue damage, and recruitment of polymorphonuclear leukocytes (PMNs). PMNs are also known to be involved in the production of specialized pro-resolving mediators (SPMs), small lipid molecules that contribute to the resolution of inflammation. This study aimed to identify target PMN-produced SPMs and interrogate their actions and potential use for therapeutic treatment after chemical injury. Our data revealed that Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexanoic acid), Lipoxin A₄ (LXA_4, 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid), and 18-HEPE ((±)-18-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid) are produced after chemical injury in the lungs, and that exogenous treatment with these SPMs reduces the acute influx of PMNs into the airspace. In a chemical lung injury model in which neutropenic mice all die within 48 hours, treatment with MaR1 or LXA₄ rescued survival of neutropenic mice to the levels of immunologically intact mice, and reduced CD11b expression, a pro-inflammatory marker, on recruited PMNs. Exogenous treatment with MaR1 or LXA₄ reduced the concentration of pro-inflammatory cytokines TNF⍺, IL6, and MCP-1 in the airspace at 24 h post-injury. These data show that exogenous treatment with MaR1 or LXA₄ ameliorates acute inflammation post-chemical lung injury and contributes to survival of severe murine aspiration pneumonia in neutropenic animals. These data have implications for treatment of sterile lung injury in immunocompromised patients.