verlukast and Peritonitis

Inflammatory mediators are released from injured tissues being responsible for the first steps of inflammatory processes. Multidrug efflux transporters, members of the ATP-binding cassette (ABC) family, are ubiquitously expressed. ABCC molecules transport several endogenous substances, including leukotriene C4 (LTC4) and PGE2, which are involved in zymosan-induced inflammation. The present study investigated the role played by ABCC transporters on zymosan-induced peritonitis in mice. Most of the resident peritoneal cells were macrophages, based on their morphology and membrane-activated complex 3 expression. RT-PCR demonstrated that these cells expressed ABCC, and ABCC activity was analyzed in vivo via the s.c. injection of ABCC inhibitors [probenecid (PROB) 200 mg/kg or MK571 20 mg/kg], followed by an i.v. injection of carboxyfluorescein diacetate (CFDA), an ABCC fluorescent substrate. Both inhibitors increased CFDA accumulation, suggesting ABCC impairment. Moreover, ABCC reversors decreased zymosan-induced plasma exudation by 86.6 +/- 7.4 and 97.6 +/- 2.3%, a feature related to a diminished secretion of LTC(4) (65.1+/-11 and 47.8+/-9.9%) and PGE(2) (under basal levels). Cell migration was inhibited similarly. Furthermore, PROB and MK571 inhibited IL-1ss by 83.4 +/- 13 and 71.2 +/- 13.4% and TNF-alpha content by 47 +/- 4.5 and 28.9 +/- 0.8%, respectively. NO metabolites and reactive oxygen species production were also reduced. The present results suggest that ABCC molecules have a relevant role in the acute inflammatory response produced by zymosan in mice.

Topics: Animals; Antigens, Differentiation; Bronchodilator Agents; Cell Movement; Chemotaxis, Leukocyte; Edema; Eicosanoids; Inflammation; Interleukin-1beta; Lipopolysaccharides; Luminescence; Macrophage Activation; Macrophages, Peritoneal; Male; Mice; Monocytes; Multidrug Resistance-Associated Proteins; Peritonitis; Propionates; Quinolines; Respiratory Burst; Tumor Necrosis Factor-alpha; Zymosan

The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO(-/-) mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB(4) receptor antagonist CP 105, 696. Protection in the 5-LO(-/-) mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.

Topics: Acidosis, Lactic; Animals; Arachidonate 5-Lipoxygenase; Capillary Permeability; Cecum; Cysteine; Disease Models, Animal; Female; Hypotension; Immunity, Innate; Leukotriene Antagonists; Leukotrienes; Ligation; Lipoxygenase Inhibitors; Male; Mice; Mice, Knockout; Peritonitis; Propionates; Punctures; Quinolines; Receptors, Leukotriene; Receptors, Leukotriene B4; Sepsis