Role of interleukin-4 in down-regulation of endothelin-1 during gastric ulcer healing: effect of sucralfate.
BACKGROUND
The course of events associaed with healing gastric mucosal injury involves an orderly interplay between the array of signaling molecules that exert their influence on the processes leading to the restoration of the mucosal integrity. In this study, we investigated the effect of antiulcer agent, sucralfate, on the mucosal apoptotic processes during gastric ulcer healing by analyzing the expression of interleukin-4 (IL:4), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the mucosal activity of capase-3, and constitutive (cNOS) and inducible nitric oxide synthase (NOS-2).


METHODS
Rats with experimentally induced chronic gastric ulcers were administered twice daily for 14 days either sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for macroscopic and biochemical assessments.


RESULTS
The ulcer onset was characterized by a massive epithelial apoptosis associated with a 33-fold increase in caspase-3 activity, 5.7-fold increase in TNF-alpha, 17.5-fold increase in NOS-2 and a 3.9-fold increase in ET-1, while the mucosal expression of cNOS activity showed a 7.6-fold drop and IL-4 expression fell by 37.2%. The healing was reflected in a rapid recovery in IL-4, and a decrease in apoptosis, caspase-3, TNF-alpha, ET-1 and NOS-2, and a slow recovery in cNOS activity, and the process was accelerated in the sucralfate-treated group. While in the absence of sucralfate the expression of IL-4 returned to that of the normal mucosa by the 7th day of healing and that of ET-1 and TNF-alpha by the 14th day, an accelerated ulcer healing with sucralfate treatment was associated with IL-4 recovery by the 4th day and that of ET-1 and TNF-alpha by the 10th day when the ulcer heated, while recovery in cNOS activity required 14 days. Yet, in both groups of animals the apoptotic DNA fragmentation rate, caspase-3 and the expression of NOS-2 activity remained significantly elevated even after the ulcer healed.


CONCLUSIONS
The results suggest that a decrease in the mucosal expression of the regulatory cytokine IL-4 at the ulcer onset may well be a key factor causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that affect the efficiency of mucosal repair process. We also show that accelerated ulcer healing by sucralfate may be the result of a rapid mucosal IL-4 generation that leads to the suppression of the mucosal apoptotic events.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey Newark, 07103-2400, USA. slomiabr@umdnj.edu
Piotrowski
J
J
Slomiany
A
A
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D015847:Interleukin-4 / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000378:metabolism / Q000503:physiopathology*; D013392:Sucralfate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D000897:Anti-Ulcer Agents; D019332:Endothelin-1; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D013392:Sucralfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases