Abstract
Trefoil factor (TFF) peptides are pivotal for gastric restitution after surface epithelial damage, but TFF cellular targets that promote cell migration are poorly understood. Conversely, Na/H exchangers (NHE) are often implicated in cellular migration but have a controversial role in gastric restitution. Using intravital microscopy to create microscopic lesions in the mouse gastric surface epithelium and directly measure epithelial restitution, we evaluated whether TFFs and NHE isoforms share a common pathway to promote epithelial repair. Blocking Na/H exchange (luminal 10 μm 5-(N-ethyl-N-isopropyl) amiloride or 25 μm HOE694) slows restitution 72-83% in wild-type or NHE1(-/-) mice. In contrast, HOE694 has no effect on the intrinsically defective gastric restitution in NHE2(-/-) mice or TFF2(-/-) mice. In TFF2(-/-) mice, NHE2 protein is reduced 23%, NHE2 remains localized to apical membranes of surface epithelium, and NHE1 protein amount or localization is unchanged. The action of topical rat TFF3 to accelerate restitution in TFF2(-/-) mice was inhibited by AMD3100 (CXCR4 receptor antagonist). Furthermore, rat TFF3 did not rescue restitution when NHE2 was inhibited [TFF2(-/-) mice +HOE694, or NHE2(-/-) mice]. HOE694 had no effect on pH at the juxtamucosal surface before or after damage. We conclude that functional NHE2, but not NHE1, is essential for mouse gastric epithelial restitution and that TFFs activate epithelial repair via NHE2.
Highlights
Trefoil factors promote tissue repair, but in vivo mechanisms are unknown
Using intravital microscopy to create microscopic lesions in the mouse gastric surface epithelium and directly measure epithelial restitution, we evaluated whether Trefoil factor (TFF) and Na/H exchangers (NHE) isoforms share a common pathway to promote epithelial repair
The work in this article seeks to understand the mechanism of action of TFFs, building on the novel observation that NHE2 activity is a required component of gastric repair
Summary
Trefoil factors promote tissue repair, but in vivo mechanisms are unknown. Results: Trefoil factors fail to stimulate repair of individual gastric lesions when NHE2 is inactivated. Conclusion: Trefoil factors require activity of a specific Na/H exchanger isoform to stimulate gastric epithelial repair. Trefoil factor (TFF) peptides are pivotal for gastric restitution after surface epithelial damage, but TFF cellular targets that promote cell migration are poorly understood. Using intravital microscopy to create microscopic lesions in the mouse gastric surface epithelium and directly measure epithelial restitution, we evaluated whether TFFs and NHE isoforms share a common pathway to promote epithelial repair. HOE694 has no effect on the intrinsically defective gastric restitution in NHE2؊/؊ mice or TFF2؊/؊ mice. Rat TFF3 did not rescue restitution when NHE2 was inhibited [TFF2؊/؊ mice ؉HOE694, or NHE2؊/؊ mice]. We conclude that functional NHE2, but not NHE1, is essential for mouse gastric epithelial restitution and that TFFs activate epithelial repair via NHE2
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