Published online before print August 24, 2004

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(Journal of Leukocyte Biology. 2004;76:961-970.)
© 2004 by Society for Leukocyte Biology

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton

Marika Collin^*, Antonietta Rossi, Salvatore Cuzzocrea, Nimesh S. A. Patel^*, Rosanna Di Paola, Julia Hadley^*, Massimo Collino^*, Lidia Sautebin and Christoph Thiemermann^*,1

^* Centre for Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, Queen Mary, University of London, United Kingdom;
Department of Experimental Pharmacology, Università ‘Federico II’, Naples, Italy; and
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy

¹ Correspondence: Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, UK. E-mail: c.thiemermann{at}qmul.ac.uk

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 ß₂-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, -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.

Key Words: shock • ß₂-integrins • CD11a/CD18 • CD11b/CD18 • leukotrienes

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