Topical Alginate Protection against Pepsin-Mediated Esophageal Damage: E-Cadherin Proteolysis and Matrix Metalloproteinase Induction

Author:

Samuels Tina L.1ORCID,Blaine-Sauer Simon1ORCID,Yan Ke2ORCID,Plehhova Kate3ORCID,Coyle Cathal3,Johnston Nikki14

Affiliation:

1. Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA

2. Department of Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA

3. Reckitt Benckiser, Hull HU8 7DS, UK

4. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

Abstract

Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, Barrett’s esophageal (BAR-T) cells were pretreated with buffered saline (HBSS; control), dilute alginate medications (Gaviscon Advance or Gaviscon Double Action, Reckitt Benckiser), a viscosity-matched placebo, or ADAM10 and matrix metalloproteinase (MMP) inhibitors before exposure to HBSS pH7.4 or pH4 ± 1 mg/mL pepsin for 10–60 min. Cell viability was assessed by ATP assay; mediators of epithelial integrity, E-cadherin, ADAM10, and MMPs were examined by Western blot and qPCR. Alginate rescued peptic reduction of cell viability (p < 0.0001). Pepsin-pH4 yielded E-cadherin fragments indicative of regulated intramembrane proteolysis (RIP) which was not rescued by inhibitors of known E-cadherin sheddases. Transcriptional targets of E-cadherin RIP fragments were elevated at 24 h (MMP-1,2,9,14; p < 0.01). Alginate rescued E-cadherin cleavage, ADAM10 maturation, and MMP induction (p < 0.01). Results support RIP as a novel mechanism of peptic injury during GERD. Alginate residue after wash-out to mimic physiologic esophageal clearance conferred lasting protection against pepsin-induced molecular mechanisms that may exacerbate GERD severity and promote carcinogenesis in the context of weakly acidic reflux.

Funder

Reckitt Benckiser UK

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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