Inhibition of sepsis-induced pancreatic injury by leukotriene receptor antagonism via modulation of oxidative injury, and downregulation of inflammatory markers in experimental rats

Abstract

Purpose The purpose of this study is to investigate the effect of montelukast on lipopolysaccharide (LPS)-induced pancreatitis. Methods Acute pancreatitis was induced by a single dose of LPS (6 mg/kg, i.p.) while montelukast was given in two different doses (10 and 20 mg/kg/day) for three consecutive days prior to injection of LPS. Results Acute pancreatitis was demonstrated by significant increases in serum levels of pancreatic enzymes lipase and amylase and lactate dehydrogenase (LDH). Proinflammatory response activation was evident by elevated serum levels of nitric oxide (NO) and increased pancreatic concentrations of tumor necrosis factor- α (TNF-α), interleukin-1 (IL-1β) and intercellular adhesion molecule-1 (ICAM-1). The activity of myeloperoxidase (MPO), a neutrophil infiltration marker, has also been increased. Oxidative stress was confirmed by significant increases in the concentrations of lipid peroxides measured as thiobarbituric acid reactive substances (TBARS) and decreases in the concentrations of reduced glutathione (GSH) in the pancreatic tissues of animals treated with LPS. Histological examination confirmed the biochemical alterations. Montelukast treatment reversed all these biochemical indices and histopathological changes that were induced by LPS. Montelukast reduced the increase in serum levels of lipase, amylase, LDH, total nitrite/nitrate, TNF-α, IL-1β and ICAM-1. MPO activities and TBARS concentrations were also suppressed while GSH content was increased in pancreatic tissues. Conclusion These results show that montelukast may be a useful pharmacological agent in protection against LPS-induced oxidative pancreatic injury by inhibiting neutrophil infiltration, counteracting oxidative stress, and suppressing inflammatory mediators.