Cysteinyl leukotriene receptor blocker, zafirlukast attenuates lipopolysaccharide -induced oxidative injury and multiple organ dysfunction in rats

ABSTRACT

Lipopolysaccharide [LPS] is a key mediator of multiple organ injury observed in septic shock. Leukotrienes have been shown to be involved in many inflammatory conditions. However, their role in septic shock has not been fully investigated. The major focus of the present study is to determine the effect of cysteinyl leukotriene blocker, zafirlukast on LPS-induced multiple organ dysfunction in experimental rats. Induction of endotoxemia for 6 h with a single intraperitoneal injection of LPS [6 mg/kg] resulted in 30% mortality rate. Animals challenged with LPS also revealed increases in serum levels of lactate dehydrogenase [LDH], a marker of systemic tissue injury, bilirubin, and serum aminotransferases, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] as measures of hepatic damage, blood urea nitrogen and serum creatinine levels [renal dysfunction indicators], creatine kinase-MB activity [heart injury indicator] and amylase [pancreatic injury measure]. Furthermore, LPS administration produced significant increases in serum levels of tumor necrosis factor-alpha [TNF- alpha], interleukin- 1 p [IL-lp], nitric oxide [NO] and intercellular adhesion molecules- 1 [ICAM-1] suggesting activation of the proinflammatory response. Oxidative stress was evident by significant increments in lipid peroxides concentrations measured as thiobarbituric acid reactive substances [TBARS] and decrements in reduced glutathione [GSH] concentrations in liver, kidney, pancreas and heart of LPS-treated animals. Myeloperoxidase [MPO] activity, a neutrophil infiltration marker, was also elevated in the same tissues. Administration of zafirlukast in two different doses [40 and 80 mg/kg/day, orally via gavage] for three consecutive days prior to LPS injection decreased LPS-induced lethality, attenuated multiple organ injury and dysfunction and reduced the increases in serum levels of TNF-alpha, IL-1beta, total nitrite/nitrate and ICAM-1. Also, MPO activities and TBARS concentrations were suppressed while GSH contents were increased in tissues. These results indicate that zafirlukast protects against LPS-induced multiple organ damage by inhibiting neutrophil infiltration, counteracting oxidative stress and suppression of inflammatory mediators. Zafirlukast may serve as a potentially effective prophylactic pharmacological agent in alleviating LPS-induced multiple organ dysfunction