Blockade of p38 mitogen-activated protein kinase pathway ameliorates delayed intestinal transit in burned rats

• Published in: The American journal of surgery 2007-04, Vol.193 (4), p.530-537
• Main Authors: Gan, Hua Tian, M.D., Ph.D, Pasricha, Pankaj J., M.D, Chen, Jiande D.Z., Ph.D
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Burn; Burns; Burns - complications; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2 (COX-2); Disease Models, Animal; Enzyme Inhibitors - pharmacology; Gastrointestinal Transit - drug effects; General aspects; Imidazoles - pharmacology; Intestinal Diseases - etiology; Intestinal Diseases - physiopathology; Intestinal transit; Kinases; Male; Medical sciences; Mortality; Nitric oxide synthase (iNOS); p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Rodents; Studies; Sulfonamides - pharmacology; Surgery; Thiourea - pharmacology; Traumas. Diseases due to physical agents
• ISSN: 0002-9610; 1879-1883
• DOI: 10.1016/j.amjsurg.2006.05.019

Abstract Background Burn injury has been shown to impair intestinal transit. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of proinflammatory mediators such as interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on intestinal transit and to elucidate its possible mechanism. Methods Burn rats and sham rats were divided into 4 groups: saline, S-methylisothiourea (a selective iNOS inhibitor), nimesulide (a selective COX-2 inhibitor), or SB203580. Intestinal transit was measured using phenol red and assessed using the geometric center. The protein or gene expression of NOS, COX-2, and IL-1β were measured by real-time reverse-transcription polymerase chain reaction or Western blot analysis. p38 MAPK activity or myeloperoxidase (MPO) activity was determined by using the p38 MAPK assay kit or MPO assay kit. Results Intestinal transit was delayed significantly with burn injury, improved significantly with S-methylisothiourea and nimesulide, but almost completely normalized with SB203580. p38 MAPK activity, MPO activity, iNOS, COX-2, and IL-1β protein or gene expression increased markedly after burn injury. SB203580 inhibited p38 MAPK and MPO activity, and reduced iNOS, COX-2, and IL-1β protein or gene expression. Conclusions Burn-induced delayed intestinal transit is associated with the p38 MAPK pathway. Inhibition of the p38 MAPK pathway ameliorates delayed intestinal transit, at least in part, by inhibiting iNOS, COX-2, and IL-1β expression. Thus, p38 MAPK could represent a novel target for therapy of gut dysmotility after burn injury.