Prophylaxis against lipopolysaccharide-induced lung injuries by liposome-entrapped dexamethasone in rats

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bac teria, stimulates phagocytes to generate metabolites that play an important role in the pathogenesis of acute lung injury. In this study, the prophyla ctic effect of liposome-entrapped dexamethasone (L-DEX) was evaluated in an animal acute lung injury model. Rats were pretreated intratracheally with L-DEX or dexamethasone phosphate (DEX) at a dose of 800 mu g dexamethasone/ kg body weight; 1 hr later, pretreated animals were challenged i.v. with LP S (Escherichia coli 0111:B4, 1 mg/kg body weight) and killed 24 hr later. C hallenge of saline-pretreated animals with LPS resulted in lung injury, as evidenced by increases in wet lung weight and decreases in lung angiotensin -converting enzyme and alkaline phosphatase activities, injury markers of p ulmonary capillary endothelial and alveolar type II epithelial cells, respe ctively. Also, LPS injection resulted in significant increases in plasma ph ospholipase A(2), thromboxane B-2, and leukotriene B-4 concentrations. The LPS challenge also increased pulmonary myeloperoxidase and elastase activit ies as well as chloramine concentrations, suggestive of neutrophil infiltra tion and activation of the inflammatory response. Pretreatment of animals w ith L-DEX was significantly more effective than pretreatment with the free drug in reducing lung inflammation and other lung injuries, as indicated by the appropriate injury markers used in this study. Our results suggested t hat the pulmonary delivery of liposome-entrapped anti-inflammatory drugs su ch as dexamethasone improves prophylactic efficacy in counteracting LPS-ind uced lung injury. (C) 2000 Elsevier Science Inc.