Cytosolic phospholipase A2 S-nitrosylation in ghrelin protection against detrimental effect of ethanol cytotoxicity on gastric mucin synthesis ——Ghrelin in gastric mucosal protection

Bronislaw L Slomiany,Amalia Slomiany

doi:10.4236/health.2010.29152

Abstract

Ghrelin, a peptide hormone produced mainly in the stomach, has emerged recently as an important regulator of nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, the products of which play direct cytoprotective function in the maintenance of gastric mucosal integrity. In this study, using gastric mucosal cells, we report on the role of ghrelin in countering the cytotoxic effect of ethanol on mucin synthesis. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and characterized by a marked up-regulation in cytosolic phospholipase A2 (cPLA2) activity. The ghrelin-induced up-regulation in mucin synthesis, like that of cPLA2 activity, was subject to suppression by Src inhibitor, PP2 and ERK inhibitor, PD98059, as well as ascorbate. Moreover, the loss in countering effect of ghrelin on the ethanol cytotoxicity and mucin synthesis was attained with cNOS inhibitor, L-NAME as well as COX-1 inhibitor SC-560. The effect of L-NAME was reflected in the inhibition of ghrelin-induced mucosal cell capacity for NO production, cPLA2 S-nitrosylation and PGE2 generation, whereas COX-1 inhibitor caused only the inhibition in PGE2 generation. Our findings suggest that the activation of gastric mucosal cPLA2 through cNOS-induced S-nitrosylation plays an essential role in the countering effect of ghrelin on the disturbances in gastric mucin synthesis caused by ethanol cytotoxicity.

Highlights

Acute gastric mucosal lesions, mucosal inflammatory changes, and gastro-duodenal ulceration are well-recognized consequences of alcohol abuse on the health of gastrointestinal tract [1,2,3]
To assess the influence of ghrelin on the disturbances in gastric mucin synthesis caused by alcohol cytotoxicity, we employed rat gastric mucosal cells exposed to ethanol at the dose range (3%) that impairs the mucosal capacity for mucin synthesis and prostaglandin generation [1,2,3]
We found that significant loss in the preventive effect of ghrelin on the ethanol-induced toxicity and the cell capacity for mucin synthesis was attained with cNOS inhibitor, L-NAME as well as specific COX-1 inhibitor, SC-560, while selective iNOS inhibitor, 1400W and a specific COX-2 inhibitor, NS-398 had no effect (Figure 3)

Summary

Introduction

Mucosal inflammatory changes, and gastro-duodenal ulceration are well-recognized consequences of alcohol abuse on the health of gastrointestinal tract [1,2,3]. Recent advances in understanding the nature of factors involved in the maintenance gastric mucosal integrity revealed that the extent of mucosal protection against ethanol cytotoxicity is influenced by ghrelin, a 28-amino acid peptide hormone produced mainly in the stomach [4,8,9]. This endogenous ligand for the growth hormone secretagogue receptor, has been implicated in the control of local inflammations, healing experimentally induced gastric ulcers, and the protection of gastric mucosa against acute injury by ethanol [4,9,10]. Ghrelin emerged as an important regulator of the cross-talk between NOS and COX enzyme systems [9], the products of which, NO and PGE2, play direct cytoprotective role in maintaining the gastric mucosal integrity under normal physiological conditions [11,12]

Methods

Results

Conclusion