Prophylaxis against lipopolysaccharide-induced lung injuries by liposome-entrapped dexamethasone in rats.
Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, stimulates phagocytes to generate metabolites that play an important role in the pathogenesis of acute lung injury. In this study, the prophylactic 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 microg dexamethasone/kg body weight; 1 hr later, pretreated animals were challenged i.v. with LPS (Escherichia coli 0111:B4, 1 mg/kg body weight) and killed 24 hr later. Challenge 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 pulmonary capillary endothelial and alveolar type II epithelial cells, respectively. Also, LPS injection resulted in significant increases in plasma phospholipase A(2), thromboxane B(2), and leukotriene B(4) concentrations. The LPS challenge also increased pulmonary myeloperoxidase and elastase activities as well as chloramine concentrations, suggestive of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with 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 that the pulmonary delivery of liposome-entrapped anti-inflammatory drugs such as dexamethasone improves prophylactic efficacy in counteracting LPS-induced lung injury.
Suntres
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Biomedical Sciences Section, Defence and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada. Zach.Suntres@dciem.dnd.ca
Shek
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PN
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002700:Chloramines / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D007975:Leukotriene B4 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008081:Liposomes; D008168:Lung / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010196:Pancreatic Elastase / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000097:blood
D000893:Anti-Inflammatory Agents; D002700:Chloramines; D004337:Drug Carriers; D008070:Lipopolysaccharides; D008081:Liposomes; D007975:Leukotriene B4; D013929:Thromboxane B2; D003907:Dexamethasone; D009195:Peroxidase; D010741:Phospholipases A; D000469:Alkaline Phosphatase; D007703:Peptidyl-Dipeptidase A; D010196:Pancreatic Elastase; C030816:chloramine