| First Author | Collin M | Year | 2004 |
| Journal | J Leukoc Biol | Volume | 76 |
| Issue | 5 | Pages | 961-70 |
| PubMed ID | 15328337 | Mgi Jnum | J:93517 |
| Mgi Id | MGI:3057227 | Doi | 10.1189/jlb.0604338 |
| Citation | Collin M, et al. (2004) Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton. J Leukoc Biol 76(5):961-70 |
| abstractText | 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 beta(2)-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. |
