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12.09.2019 | Original Article

Deficient Active Transport Activity in Healing Mucosa After Mild Gastric Epithelial Damage

Zeitschrift:
Digestive Diseases and Sciences
Autoren:
Andrea L. Matthis, Izumi Kaji, Kristen A. Engevik, Yasutada Akiba, Jonathan D. Kaunitz, Marshall H. Montrose, Eitaro Aihara
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s10620-019-05825-x) contains supplementary material, which is available to authorized users.

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Abstract

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, 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).

Results

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.

Conclusion

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.

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Zusatzmaterial
Supplementary Fig. 1. Hypertonic NaCl effect on resistance. Wild-type mouse muscle-stripped gastric corpus was mounted into an Ussing chamber (area = 0.1 cm2) and transepithelial R were measured as described in Methods. Representative time course of percent (%) normalized R after addition of 0 M (black), 0.25 M (green), 0.5 M (blue), or 1.0 M (red) NaCl to luminal nutrient solution. Time zero starts 10 min baseline measurement prior to 5 min (NaCl arrow) exposure to NaCl challenge. At t = 30 min (arrow) shows the time point where change in (Δ) R at 15 min post-NaCl was calculated. (JPEG 176 kb)
10620_2019_5825_MOESM1_ESM.jpg
Supplementary Fig. 2. Controls for artifacts during 0.5 M NaCl challenge. After reaching Isc steady state while either a glass coverslip (A) or permeable plastic wrap (B) was mounted in an Ussing chamber, 0.5 M NaCl was added luminally for 5 min (arrow). Outcomes identify Isc changes caused by solution changes that are distinct from tissue active ion transport. (JPEG 170 kb)
10620_2019_5825_MOESM2_ESM.jpg
Literatur
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