title: Trefoil factor 2 requires Na/H exchanger 2 activity to enhance mouse gastric epithelial repair.
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.
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267.
authors: Lin
authors: L
authors: Xue
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267.
authors: Eitaro
authors: E
authors: Aihara
authors: Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York 10032.
authors: Timothy C
authors: TC
authors: Wang
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267. Electronic address: mhm@uc.edu.
authors: Marshall H
authors: MH
authors: Montrose
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000166:cytology*; D005753:Gastric Mucosa / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D009077:Mucins / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D000071164:Trefoil Factor-2; D014945:Wound Healing
chemical_list: D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D010750:Phosphoproteins; D019718:Receptors, CXCR4; C513111:Slc9a2 protein, mouse; D017923:Sodium-Hydrogen Exchangers; C481546:TFF2 protein, mouse; C000604008:Tff2 protein, rat; D000071164:Trefoil Factor-2; C093376:sodium-hydrogen exchanger regulatory factor