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Published ahead of print on March 2, 2006, doi:10.1164/rccm.200511-1737OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 10, May 2006, 1130-1138

A more recent version of this article appeared on May 15, 2006
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Submitted on November 10, 2005
Accepted on February 24, 2006

Oxidized Phospholipids Reduce Vascular Leak and Inflammation in Rat Model of Acute Lung Injury

Stephanie Nonas1, Ian Miller1, Kamon Kawkitinarong1, Santipongse Chatchavalvanich2, Irina Gorshkova2, Valery N Bochkov3, Norbert Leitinger4, Viswanathan Natarajan2, Joe G.N. Garcia2, and Konstantin G Birukov2*

1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Department Medicine, University of Chicago, Chicago, IL, USA, 3 Department of Vascular Biology and Thrombosis Research, University of Vienna, Vienna, Austria, 4 Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA

* To whom correspondence should be addressed. E-mail: kbirukov{at}medicine.bsd.uchicago.edu.

Rationale: Acute inflammation and vascular leak are cardinal features of acute lung injury and the acute respiratory distress syndrome. Non-specific tissue inflammation and injury in response to infectious and non-infectious insults leads to oxidative stress and the generation of lipid oxidation products, which may inhibit the acute inflammatory response to bacterial components. Objective: To test the hypothesis that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) may attenuate the acute lung inflammatory response to lipopolysaccharide and enhance lung vascular barrier recovery, we used in vivo and in vitro models of lipopolysaccharide-induced lung injury. Methods: Rats received intratracheal aerosolized lipopolysaccharide (5 mg/kg) or sterile water with concurrent intravenous injection of OxPAPC (0.5-6.0 mg/kg) or saline alone. Non-oxidized PAPC was used as control. At 18 hours, bronchoalveolar lavage was performed and the lungs were removed for histological analysis. Measurements of endothelial transmonolayer electrical resistance and immunofluorescent analysis of monolayer integrity were used in an in vitro model of lipopolysaccharide-induced lung vascular barrier dysfunction. Measurements and Main Results: In vivo, aerosolized intratracheal lipopolysaccharide induced lung injury with profound increases in bronchoalveolar lavage neutrophils, protein content, and the inflammatory cytokines IL-6 and IL-1{beta}, as well as tissue neutrophils. OxPAPC, but not non-oxidized PAPC, markedly attenuated the lipopolysaccharide-induced tissue inflammation, barrier disruption, and cytokine production over a range of doses. In vitro, oxidized phospholipids attenuated lipopolysaccharide-induced endothelial barrier disruption and reversed lipopolysaccharide-induced cytoskeletal remodeling and disruption of monolayer integrity. Conclusions: These studies demonstrate in vivo and in vitro protective effects of oxidized phospholipids on lipopolysaccharide-induced lung dysfunction.
Key words: bacterial wall lipopolysaccharide, IL6, IL1-{beta}, bronchoalveolar lavage, lung endothelial permeability




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