Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.
The role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX(-/-)) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of beta2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry. Zileuton [3 mg/kg intravenously (i.v.)] or vehicle (10% dimethyl sulfoxide) was administered to rats 15 min prior to lipopolysaccharide (LPS; Escherichia coli, 6 mg/kg i.v.) or vehicle (saline). 5-LOX(-/-) mice and wild-type littermate controls were treated with LPS (E. coli, 20 mg/kg intraperitoneally) or vehicle (saline). Endotoxemia for 6 h in rats or 16 h in mice resulted in liver injury/dysfunction (increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin), renal dysfunction (creatinine), and pancreatic injury (lipase, amylase). Absence of functional 5-LOX (zileuton treatment or targeted disruption of the 5-LOX gene) reduced the multiple organ injury/dysfunction caused by endotoxemia. Polymorphonuclear leukocyte infiltration (myeloperoxidase activity) in the lung and ileum as well as pulmonary injury (histology) were markedly reduced in 5-LOX(-/-) mice. Zileuton also reduced the LPS-induced expression of CD11b/CD18 on rat leukocytes. We propose that endogenous 5-LOX metabolites enhance the degree of multiple organ injury/dysfunction caused by severe endotoxemia by promoting the expression of the adhesion molecule CD11b/CD18 and that inhibitors of 5-LOX may be useful in the therapy of the organ injury/dysfunction associated with endotoxic shock.
Collin
Marika
M
Centre for Experimental Medicine, Nephrology and Critical Care, The William Harvey Research Institute, Queen Mary, University of London, UK.
Rossi
Antonietta
A
Cuzzocrea
Salvatore
S
Patel
Nimesh S A
NS
Di Paola
Rosanna
R
Hadley
Julia
J
Collino
Massimo
M
Sautebin
Lidia
L
Thiemermann
Christoph
C
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D018845:CD11 Antigens / Q000187:drug effects / Q000276:immunology; D018821:CD18 Antigens / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004798:Enzymes / Q000097:blood / Q000187:drug effects; D018390:Gene Targeting; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D014781:Viscera / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology
D018845:CD11 Antigens; D018821:CD18 Antigens; D004798:Enzymes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea