Interaction of epidermal growth factor with COX-2 products and peroxisome proliferator-activated receptor-γ system in experimental rat Barrett’s esophagus

Abstract

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1β, TNFα, and mucosal PGE2 content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE. NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.

Molecular Profile of Barrett’s Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies

“…Therefore, the development of novel or alternative pharmacological therapeutic interventions seems to be justified, also taking into account the recently published evidence [5]. Current advances in the understanding of the complex molecular mechanisms of BE development, which came from experimental models of BE, include overexpression of cyclooxygenase-2 (COX-2) [15,16], epidermal growth factor (EGF) [17][18][19], or mitogen-activated protein kinase (MAPK) and the protein kinase phosphorylation (PI3K) pathways [20,21], as well as increased secretion of gastrin due to achlorhydria as a complication of prolonged proton pomp inhibitors (PPI) therapy [22]. However, many ongoing controversies and challenges and potential mediators responsible for the development of BE still remain unsolved.…”

Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

“…The existence of an intracellular cross-talk between the EGFR and COX-2 pathways has been demonstrated in previous studies. [75][76][77] Pai et al [25] believed that PGE2 exerts trophic actions on gastric and intestinal mucosa, resulting in gastrointestinal hypertrophy via PGE2/ EGFR/ERK1/2 signaling. In this study, TST-treated rats exhibited a high activity of COX-2 accompanied by elevated ERK1/2 phosphorylation.…”