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Inhibition of p38 MAPK improves intestinal disturbances and oxidative stress induced in a rabbit endotoxemia model
S Gonzalo1, L Grasa, M P Arruebo
1Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain.
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.
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.
Insights
Lipopolysaccharide (LPS) reduces rabbit duodenal contractility and increases oxidative stress by activating p38 MAPK. Inhibiting p38 MAPK with SB203580 reversed these LPS-induced effects, highlighting p38 MAPK
Area of Science:
- Gastroenterology
- Molecular Biology
- Pathophysiology
Background:
- Lipopolysaccharide (LPS) impairs intestinal contractility and elevates reactive oxygen species, contributing to sepsis pathogenesis.
- p38 mitogen-activated protein kinase (MAPK) is activated by stimuli like LPS.
- The role of p38 MAPK in LPS-induced duodenal dysfunction and oxidative stress requires elucidation.
Purpose of the Study:
- To investigate the involvement of p38 MAPK in LPS-induced alterations of duodenal contractility.
- To assess the impact of LPS on oxidative stress markers in the intestine.
- To determine the localization of active p38 MAPK within the duodenal tissue.
Main Methods:
- Rabbit duodenal contractility was assessed using organ bath studies following administration of LPS and/or the p38 MAPK inhibitor SB203580.
- Protein expression of phospho-p38 (p-p38) and total p38 was analyzed via Western blot.
- Oxidative stress markers, including protein carbonyls and MDA+4-HDA, were quantified in intestinal and plasma samples. Immunohistochemistry localized p-p38.
Main Results:
- LPS significantly reduced acetylcholine, prostaglandin E(2), and KCl-induced duodenal contractions.
- LPS elevated phospho-p38 expression and increased levels of protein carbonyls and MDA+4-HDA.
- SB203580 effectively counteracted the effects of LPS on duodenal contractility and oxidative stress markers, both in vivo and in vitro. P-p38 was localized in myenteric plexus neurons and smooth muscle cells.
Conclusions:
- p38 MAPK acts as a key mediator in LPS-induced decreases in duodenal contractility.
- LPS-induced oxidative stress in the intestine is significantly influenced by p38 MAPK activation.
- Targeting p38 MAPK may offer a therapeutic strategy for managing sepsis-related gastrointestinal dysfunction.
