title: Intestinal effects of lipopolysaccharide in rabbit are mediated by cyclooxygenase-2 through p38 mitogen activated protein kinase.
abstract: The mediators of the pathophysiological symptoms of septic shock are not completely understood. The intracellular signalling mechanisms of lipopolysaccharide (LPS)-induced effects need further investigation. This study investigates (1) the role of COX-2 in the effect of LPS on (a) the KCl, acetylcholine and prostaglandin E₂-induced contractions of rabbit duodenum and (b) the oxidative stress status in plasma and intestine and (2) the relationship between p38 MAPK and COX-2 expression in rabbit duodenum. Rabbits were injected i.v. with either (1) saline, (2) LPS, (3) SB203580, a p38 MAPK inhibitor, (4) SB203580+LPS, (5) NS-398, a COX-2 inhibitor or (6) NS-398+LPS. Contractility studies were performed by suspending pieces of duodenum in an organ bath in the direction of longitudinal and circular smooth muscle fibres. The formation of products of oxidative damage to proteins (carbonyls) and lipids [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] was quantified in intestinal tissue and plasma. The protein expression of COX-2 was measured by western blot. The KCl, acetylcholine and prostaglandin E₂-induced contractions decreased with LPS. In addition, LPS increased the levels of carbonyls and MDA+4-HDA in plasma and duodenum as well as COX-2 expression in duodenal tissue. All these effects were blocked by NS-398. The p38 MAPK inhibitor SB203580 blocked the effect of LPS on COX-2 expression. These results suggest that the effect of LPS on KCl, acetylcholine and prostaglandin E₂-induced contractions in the rabbit duodenum and oxidative stress might be mediated by an increase in COX-2 expression through the p38 MAPK pathway.
authors.affiliation: Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonzalo
authors.forename: Laura
authors.initials: L
authors.lastname: Grasa
authors.forename: Diego Santos
authors.initials: DS
authors.lastname: Fagundes
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Arruebo
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Plaza
authors.forename: María Divina
authors.initials: MD
authors.lastname: Murillo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011189:Potassium Chloride; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D000109:Acetylcholine