Deficient Active Transport Activity in Healing Mucosa After Mild Gastric Epithelial Damage
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Peptic ulcers recur, suggesting that ulcer healing may leave tissue predisposed to subsequent damage. In mice, we have identified that the regenerated epithelium found after ulcer healing will remain abnormal for months after healing.
To determine whether healed gastric mucosa has altered epithelial function, as measured by electrophysiologic parameters.
Ulcers were induced in mouse gastric corpus by serosal local application of acetic acid. Thirty days or 8 months after ulcer induction, tissue was mounted in an Ussing chamber. Transepithelial electrophysiologic parameters (short-circuit current, Isc. resistance, R) were compared between the regenerated healed ulcer region and the non-ulcerated contralateral region, in response to luminal hyperosmolar NaCl challenge (0.5 M).
In unperturbed stomach, luminal application of hyperosmolar NaCl transiently dropped Isc followed by gradual recovery over 2 h. Compared to the starting baseline Isc, percent Isc recovery was reduced in 30-day healing mucosa, but not at 8 months. Prior to NaCl challenge, a lower baseline Isc was observed in trefoil factor 2 (TFF2) knockout (KO) versus wild type (WT), with no Isc recovery in either non-ulcerated or healing mucosa of KO. Inhibiting Na/H exchanger (NHE) transport in WT mucosa inhibited Isc recovery in response to luminal challenge. NHE2-KO baseline Isc was reduced versus NHE2-WT. In murine gastric organoids, NHE inhibition slowed recovery of intracellular pH and delayed the repair of photic induced damage.
Healing gastric mucosa has deficient electrophysiological recovery in response to hypertonic NaCl. TFF2 and NHE2 contribute to Isc regulation, and the recovery and healing of transepithelial function.
KeywordsUlcer Gastric Epithelial cell Repair TFF2 NHE2 Ussing chamber Confocal microscopy Photodamage Actin
We thank H.J. Lang, PhD (Aventis Pharma Deutschland) for the generous gift of HOE 694, John Cuppoletti, PhD (University of Cincinnati) for supplying the Ussing chamber, and Chet Closson (University of Cincinnati) for technical assistance with the microscopes. We are very grateful to Timothy C. Wang, MD (Columbia University) for supplying the TFF2-KO, Gary E. Shull, PhD and Roger T. Worrell, PhD (University of Cincinnati) for supplying the NHE2-KO, and Walter Witke, PhD and Jerrold R. Turner, MD, PhD for supplying the HuGE mice.
This work was supported by the National Institutes of Health (NIH) grant R01DK102551 (M.H.M., E.A.), the University of Cincinnati Research Council Faculty Research Grant (E.A.), Ryuji Ueno Award co-sponsored by the S&R Foundation and American Physiological Society (E.A.), and a VA Merit Award to JDK. This project was also supported in part by the NIH P30 DK078392; Live Microscopy Core and DNA Sequencing and Genotyping Core of the Digestive Disease Research Core Center in Cincinnati.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal rights
All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of the University of Cincinnati. This article does not contain any studies with human participants performed by any of the authors.
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