Acute inflammation and vascular leak are cardinal features of acute lung injury and the acute respiratory distress syndrome. Nonspecific tissue inflammation and injury in response to infectious and noninfectious insults lead to oxidative stress and the generation of lipid oxidation products, which, in turn, may inhibit the acute inflammatory response to bacterial components. In this study, we used animal and endothelial cell culture models of lipopolysaccharide-induced lung injury to test the hypothesis that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine may attenuate the acute lung inflammatory response to bacterial wall lipopolysaccharide (LPS) and enhance lung vascular barrier recovery. Rats received aerosolized LPS (5 mg/kg) or sterile water with concurrent intravenous oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (0.5-6 mg/kg) or saline. At 18 hours, bronchoalveolar lavage was performed and the lungs were removed for histological analysis. Measurements of transendothelial electrical resistance and histochemical analysis of endothelial monolayer disruption were used as an in vitro model of LPS-induced lung barrier dysfunction. Intratracheal instillation of LPS induced lung injury with profound increases in bronchoalveolar lavage and tissue neutrophils, protein content, and production of inflammatory cytokines IL-6 and IL-1b. Intravenous injection of oxidized phospholipids markedly attenuated LPS-induced tissue inflammation, barrier disruption, and IL-6 and IL-1b production over a range of doses. In vitro, oxidized phospholipids attenuated LPS-induced endothelial permeability and reversed LPS-induced cytoskeletal remodeling and disruption of monolayer integrity. These studies demonstrate in vivo and in vitro protective effects of oxidized phospholipids on LPS-induced lung dysfunction.
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