Secretory Phospholipase A2 Inhibition Attenuates Adhesive Properties of Esophageal Barrett's Cells

Abstract

Background: Gastroesophageal reflux and Barrett's esophagus are significant risk factors for the development of esophageal adenocarcinoma. Group IIa secretory phospholipase A₂ (sPLA₂) catalyzes the production of various proinflammatory metabolites and plays a critical role in promoting reflux-induced inflammatory changes within the distal esophagus. We hypothesized that inhibition of sPLA₂ in human Barrett's cells would attenuate adhesion molecule expression via decreased activation of nuclear factor kappa B (NF-κB) and decrease cell proliferation, possibly mitigating the invasive potential of Barrett's esophagus.

Materials and methods: Normal human esophageal epithelial cells (HET1A) and Barrett's cells (CPB) were assayed for baseline sPLA₂ expression. CPB cells were treated with a specific inhibitor of sPLA₂ followed by tumor necrosis factor-α. Protein expression was evaluated using immunoblotting. Cell proliferation was assessed using an MTS cell proliferation assay kit. Statistical analysis was performed using the Student's t-test or analysis of variance, where appropriate.

Results: CPB cells demonstrated higher baseline sPLA₂ expression than HET1A cells (P = 0.0005). Treatment with 30 μM sPLA₂ inhibitor significantly attenuated intercellular adhesion molecule-1 (P = 0.004) and vascular cell adhesion molecule-1 (P < 0.0001) expression as well as decreased NF-κB activation (P = 0.002). sPLA₂ inhibition decreased cell proliferation in a dose-dependent manner (P < 0.001 for 15, 20, and 30 μM doses).

Conclusions: sPLA₂ inhibition in human Barrett's cells decreases cellular adhesive properties and NF-κB activation as well as decreases cell proliferation, signifying downregulation of the inflammatory response and possible attenuation of cellular malignant potential. These findings identify sPLA₂ inhibition as a potential chemopreventive target for premalignant lesions of the esophagus.

Keywords: Barrett's esophagus; Intercellular adhesion molecule-1; Proliferation; Secretory phospholipase A(2); Vascular cell adhesion molecule-1.