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

Abstract

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.

Intravenous anesthetic propofol suppresses leukotriene production in murine dendritic cells

“…Besides the possible benefit in asthma patients, there are plenty of theoretical clinical benefits related to the suppression of leukotriene production with propofol. Examples include the reduction of the multiple organ injury and dysfunction in endotoxemia (Collin et al, 2004;Rossi et al, 2009) and the reduction of metastasis after tumor extirpation surgery (Sethi et al, 2012). These implications are very intriguing, but are obviously too speculative and further study is definitely needed.…”

IL-12, but Not IL-18, Is Critical to Neutrophil Activation and Resistance to Polymicrobial Sepsis Induced by Cecal Ligation and Puncture

“…Consistent with the inability of SL-CLP IL-12 Ϫ/Ϫ mice to control the infection, these mice showed elevated systemic inflammation, similar to that observed in WT mice given lethal CLP. It is important to note that neutrophil infiltration in distant organs of the infectious focus, such as lung, contributes to the tissue damage, multiple organ failure, and consequently to death of the host in the sepsis (48,49). An earlier report showed that polyclonal anti-IL-12 Ab did not interfere with the mortality of mice given CLP or i.p.…”

Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

“…Like MyD88, LTB 4 has also been implicated in antimicrobial defense as well as a variety of inflammatory disease states, such as atherosclerosis, ischemia-reperfusion injury, and immune responses (12). 5-LO metabolites have been suggested to participate in in vivo and in vitro LPS responses (14), but these reports were limited by the off-target effects of the pharmacologic inhibitors used (15) and by ambiguity regarding the specific 5-LO products required for TLR responses (14,(16)(17)(18). The role of specific 5-LO metabolites and receptors in various TLR- and cytokine receptor-mediated responses is therefore poorly understood.…”