Inhibition of p38 MAPK activation attenuates esophageal mucosal damage in a chronic model of reflux esophagitis.
BACKGROUND
Reflux esophagitis (RE) is one of the common gastrointestinal diseases that are increasingly recognized as a significant health problem. This study was designed to investigate the role of p38 mitogen-activated protein kinase (MAPK) in experimental chronic RE model of rats.


METHODS
Chronic acid RE rats were induced by fundus ligation and partial obstruction of the pylorus and treated with SB203580 (a p38 MAPK inhibitor, i.p., 1 mg/kg/day) for 14 days.


RESULTS
Immunohistochemical staining and Western blotting results revealed the activation of p38 MAPK signaling in the esophagus mucosa 14 days post injury. Through gross and histological assessment, we found that inhibition of p38 MAPK activation by SB203580 attenuated esophageal mucosal damage in RE rats. Inhibition of p38 MAPK activation in RE rats attenuated esophageal barrier dysfunction, through enhancing the expression of tight junction proteins and reducing the expression of matrix matalloproteinases-3 and -9. Inhibition of p38 MAPK activation in RE rats reduced CD68-positive cells in esophagus mucosa and mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in esophagus and protein levels of TNF-α, IL-6, and IL-1β in serum. In addition, we found that inhibition of p38 MAPK activation in RE rats suppressed protein expression of inducible nitric oxide synthase and reduced formation of nitric oxide (NO), 3-nitrotyrosin, and malondialdehyde in esophagus.


CONCLUSIONS
Inhibition of p38 MAPK activation attenuated esophageal mucosal damage in acid RE rats, possibly by modulating esophageal barrier function and regulating inflammatory cell recruitment, and the subsequent formation of cytokines, NO, and reactive oxygen species.
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
L
L
Zhang
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.|Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China.
G
G
Liu
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
X
X
Han
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
J
J
Liu
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
G-X
GX
Li
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
D-W
DW
Zou
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Z-S
ZS
Li
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004942:Esophagitis, Peptic / Q000201:enzymology* / Q000473:pathology*; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
acid reflux esophagitis; inflammation; p38 MAPK; rats