UCLA

Background

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.

Aim

To determine whether healed gastric mucosa has altered epithelial function, as measured by electrophysiologic parameters.

Method

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, I_sc. 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).

Results

In unperturbed stomach, luminal application of hyperosmolar NaCl transiently dropped I_sc followed by gradual recovery over 2 h. Compared to the starting baseline I_sc, percent I_sc recovery was reduced in 30-day healing mucosa, but not at 8 months. Prior to NaCl challenge, a lower baseline I_sc was observed in trefoil factor 2 (TFF2) knockout (KO) versus wild type (WT), with no I_sc recovery in either non-ulcerated or healing mucosa of KO. Inhibiting Na/H exchanger (NHE) transport in WT mucosa inhibited I_sc recovery in response to luminal challenge. NHE2-KO baseline I_sc was reduced versus NHE2-WT. In murine gastric organoids, NHE inhibition slowed recovery of intracellular pH and delayed the repair of photic induced damage.

Conclusion

Healing gastric mucosa has deficient electrophysiological recovery in response to hypertonic NaCl. TFF2 and NHE2 contribute to I_sc regulation, and the recovery and healing of transepithelial function.