Trefoil Peptides: Mitogens, Motogens, or Mirages?

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Abstract
Healing of mucosal damage occurs in two phases: restitution of mucosal integrity followed by remodeling with recreation of mucosal architecture. Models of these phenomena include cryoprobe-induced ulcers, NSAID lesions, and surgical anastomosis. Three trefoil peptides are expressed constitutively by epithelial cells in specific regions of the GI tract: pS2 (gastric), spasmolytic polypeptide (SP, gastric and Brunner's glands), and intestinal trefoil factor (ITF, goblet cells). Altered expression occurs in reparative epithelium and adjacent mucosa. In cryoprobe ulceration, rSP mRNA abundance doubles within 2 h, with rITF mRNA becoming detectable after 2-3 days. TGF-alpha and EGF mRNAs do not increase as rapidly as rSP or to the same extent as rITF. Indomethacin lesions of gastric mucosa show increased SP immunoreactivity deep in damaged glands within hours. Surgical anastomotic damage increases rITF mRNA levels at the ulcer edge and sometimes rSP mRNA and peptide in para-anastomotic crypts. Initially, trefoil peptides were viewed as mitogens. However, they are in fact motogens, able to promote cell migration, and may possibly be morphogens. Interactions occur between trefoils and other wound healing peptides (FGFs and EGF). Trefoil peptides appear to be of considerable importance to mucosal healing and might constitute a biologic target of therapeutic relevance.