Inhibition of p38 MAPK improves intestinal disturbances and oxidative stress induced in a rabbit endotoxemia model

Background Lipopolysaccharide (LPS) decreases intestinal contractility and induces the release of reactive oxygen species, which play an important role in the pathogenesis of sepsis. p38 mitogen-activated protein kinase (MAPK) can be activated by a variety of stimuli such as LPS. The aims of this study were: (i) to investigate the role of p38 MAPK in the effect of LPS on (a) the acetylcholine, prostaglandin E(2) and KCl-induced contractions of rabbit duodenum and (b) the oxidative stress status; (ii) to localize the active form of p38 in the intestine. Methods Rabbits were injected with (i) saline, (ii) LPS, (iii) SB203580, a specific p38 MAPK inhibitor or (iv) SB203580 + LPS. Duodenal contractility was studied in an organ bath. SB203580 was also tested in vitro. The protein expression of p-p38 and total p38 was measured by Western blot and p-p38 was localized by inmunohistochemistry. The formation of products of oxidative damage to proteins (carbonyls) and lipids (MDA+4-HDA) was quantified in intestine and plasma. Key Results ACh, PGE(2) and KCl-induced contractions decreased with LPS. LPS increased phospho-p38 expression and the levels of carbonyls and MDA+4-HDA. SB203580 blocked the effect of LPS on the ACh, PGE(2) and KCl-induced contractions in vivo and in vitro and the levels of carbonyls and MDA+4-HDA. P-p38 was detected in neurons of the myenteric plexus and smooth muscle cells of duodenum. Conclusions & Inferences Lipopolysaccharide decreases the duodenal contractility in rabbits and increases the production of free radicals. p38 MAPK is a mediator of these effects.