Extracellular signal-regulated kinase (ERK) is involved in LPS-induced disturbances in intestinal motility

Abstract

Lipopolysaccharide (LPS) is a causative agent of sepsis. A relationship has been described between LPS, free radicals, and cyclooxygenase-2 (COX-2). Here, we investigate the role of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPK) in the effect of LPS on intestinal motility, oxidative stress status, and COX-2 expression. Rabbits were injected with (i) saline, (ii) LPS, (iii) U0126, an ERK MAPK inhibitor, or (iv) U0126+LPS. Duodenal contractility was studied in an organ bath with acetylcholine, prostaglandin E(2), and KCl added. Neuromuscular function was assessed by electrical field stimulation (EFS). Neurotransmitter blockers were used to study the EFS-elicited contractile response. The formation of products of oxidative damage to proteins (carbonyls), lipids, [malondialdehyde (MDA), and 4-hydroxyalkenals (4-HDA)] was quantified in plasma and intestine. The protein expression of phospho-ERK (p-ERK), total ERK, and COX-2 in the intestine was measured by western blot, and p-ERK was localized by immunohistochemistry. Acetylcholine, prostaglandin E(2), and KCl-induced contractions decreased with LPS. Electrical field stimulation induced a neurogenic contraction that was reduced by LPS. Lipopolysaccharide increased p-ERK and COX-2 expression and the levels of carbonyls and MDA+4-HDA. U0126 blocked the effect of LPS on acetylcholine, prostaglandin E(2), KCl, and EFS-induced contractions, the levels of carbonyls and MDA+4-HDA and p-ERK and COX-2 expression. Phospho-ERK was detected mostly in the neurons of the myenteric and submucosal ganglia. We can suggest that ERK is involved in the mechanism of action of LPS in the intestine.