Resolution Of Experimental Lung Injury Delayed By Sustained Expression Of Alveolar Macrophage CD86

Abstract

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

Callicarpa japonica Thunb. reduces inflammatory responses: A mouse model of lipopolysaccharide-induced acute lung injury

“…Previous studies have published results in which they demon-303 strated that iNOS knockout mice have less lung inflammation compared 304with wild-type mice[26]. Speyer et al[27] and D'Alessio et al[28] …”