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 immunohistochemistry. The formation of products of oxidative damage to proteins (carbonyls) and lipids (MDA+4-HDA) was quantified in intestine and plasma.


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
Lipopolysaccharide decreases the duodenal contractility in rabbits and increases the production of free radicals. p38 MAPK is a mediator of these effects.
Gonzalo
S
S
Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain.
Grasa
L
L
Arruebo
M P
MP
Plaza
M A
MA
Murillo
M D
MD
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004386:Duodenum / Q000187:drug effects* / Q000503:physiopathology; D019446:Endotoxemia / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580