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In contrast to the wealth of information cellular and molecular mechanisms that cause acute lung injury (ALI), relatively little is known about mechanism of resolution. Alveolar macrophages (AM) play a critical role in the pathogenesis of ALI, however their role in resolution of ALI is unknown. In a mouse model of lung injury using intratracheal lipopolysaccharide (i.t. LPS 3.75 mg/kg; normal dose), we have previously shown that mice have unremitting lung inflammation as late as 7 days after ALI in contrast to their WT counterparts. We iNOS -/rigorously phenotyped alveolar macrophages using multicolor flow cytometry, and observed that AM from mice displayed iNOS -/sustained expression of the co-signalling molecule CD86. Anti-CD86 antibodies (intraperitoneal) 48 hours after LPS produced normal resolution of ALI in mice, confirming a functional role. To determine if CD86 participates in the lung injury response in WT mice, we iNOS -/administered high dose LPS (i.t. LPS 6 mg/kg) followed 48 hours later by isotype or anti-CD86 antibodies. WT animals have complete resolution of lung injury by day 7 after normal dose LPS, however lung injury after high dose LPS did not resolve by day 7 in WT animals receiving isotype antibodies, with persistent weight loss, increased BAL protein, BAL cell counts and neutrophils. Lung histological sections showed persistent alveolar damage and marked interstitial thickening at day 7 in the high-dose, but not the normal dose LPS group. Flow cytometry showed a marked reduction of alveolar Regulatory T cells after high dose LPS, with high level expression of BAL macrophage CD86 in the high-dose group. Antibody-mediated blockade of CD86 restored resolution of lung injury by day 7, while inducing a 20-fold increase in the number of alveolar Regulatory T cells. We propose that CD86 may be a downstream target whose regulation is critical to resolution of lung injury. This abstract is funded by: NHLBI K99HL103973

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