Oxidized phospholipids reduce vascular leak and inflammation in rat model of acute lung injury.

Abstract

RATIONALE:

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 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 (LPS) and enhance lung vascular barrier recovery, we used in vivo and in vitro models of LPS-induced lung injury.

METHODS:

Rats received intratracheal aerosolized LPS (5 mg/kg) or sterile water with concurrent intravenous injection of OxPAPC (0.5-6.0 mg/kg) or saline alone. Nonoxidized PAPC was used as a control. At 18 h, bronchoalveolar lavage was performed and the lungs were removed for histologic analysis. Measurements of endothelial transmonolayer electrical resistance and immunofluorescent analysis of monolayer integrity were used in an in vitro model of LPS-induced lung vascular barrier dysfunction.

MEASUREMENTS AND MAIN RESULTS:

In vivo, aerosolized intratracheal LPS induced lung injury with profound increases in bronchoalveolar lavage neutrophils, protein content, and the inflammatory cytokines interleukin 6 and interleukin 1beta, as well as tissue neutrophils. OxPAPC, but not nonoxidized PAPC, markedly attenuated the LPS-induced tissue inflammation, barrier disruption, and cytokine production over a range of doses. In vitro, oxidized phospholipids attenuated LPS-induced endothelial barrier disruption and reversed LPS-induced cytoskeletal remodeling and disruption of monolayer integrity.

CONCLUSIONS:

These studies demonstrate in vivo and in vitro protective effects of oxidized phospholipids on LPS-induced lung dysfunction.

• Authors: Stephanie Nonas, Ian Miller, Kamon Kawkitinarong, Santipongse Chatchavalvanich, Irina Gorshkova, Valery N Bochkov, Norbert Leitinger, Viswanathan Natarajan, Joe G N Garcia, Konstantin G Birukov
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 173 Issue 10 Pg. 1130-8 (May 15 2006) ISSN: 1073-449X [Print] United States
• PMID: 16514111 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Inflammation Mediators
• Interleukin-1
• Interleukin-6
• Lipopolysaccharides
• Phosphatidylcholines
• oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine

Topics

• Animals
• Biopsy, Needle
• Bronchoalveolar Lavage Fluid (cytology)
• Capillary Permeability (drug effects)
• Cytokines (analysis)
• Disease Models, Animal
• Immunohistochemistry
• Inflammation Mediators (analysis)
• Interleukin-1 (analysis)
• Interleukin-6 (analysis)
• Lipopolysaccharides
• Male
• Phosphatidylcholines (pharmacology)
• Probability
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Respiratory Distress Syndrome (drug therapy, pathology)
• Sensitivity and Specificity