title: Insights into the mechanisms of gastric adaptation to aspirin-induced injury: a role for regenerating protein but not trefoil peptides.
abstract: The phenomenon of reduced gastric mucosal injury despite repeated doses of a damaging agent is termed adaptation. Adaptation to nonsteroidal anti-inflammatory drug-induced injury has been clearly demonstrated in both humans and experimental animals; however, the precise mechanisms remain unclear. We hypothesized that mediators of adaptation might be the regenerating protein (RegI) and the trefoil peptides TFF1 and TFF2, because these proteins play pivotal roles in gastric mucosal protection and repair. The gene expression and the protein levels of these proteins were measured and compared in normal, aspirin-injured, and aspirin-adapted rat stomachs. TFF gene and protein expression levels were similar in all three groups, whereas RegI gene expression and protein levels in adapted stomach were increased. A time course analysis of RegI expression during the onset and offset of adaptation showed that mucosal RegI increased during the development of adaptation, was maintained during subsequent aspirin dosing, and returned to baseline levels once dosing had ceased and adaptation was lost-indicative of a causal role in the adaptation process. Colocalization of increased RegI with gastric epithelial areas showing increased proliferation also suggests that RegI may be an important mediator of the resolution of mucosal injury that is characteristic of gastric adaptation to aspirin.
authors.affiliation: University of Melbourne, Department of Medicine, Western Hospital, Footscray, Victoria, Australia.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Alderman
authors.forename: Meera
authors.initials: M
authors.lastname: Ulaganathan
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.forename: Meegan
authors.initials: M
authors.lastname: Howlett
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Parker
authors.forename: Neville D
authors.initials: ND
authors.lastname: Yeomans
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001241:Aspirin / Q000633:toxicity*; D015152:Blotting, Northern; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051847:Lithostathine; D009077:Mucins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000187:drug effects; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D006133:Growth Substances; D051847:Lithostathine; D009077:Mucins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; C497616:Reg1a protein, rat; C051838:TFF1 protein, human; C000604007:TFF2 protein, human; C099037:TFF3 protein, rat; C000604008:Tff2 protein, rat; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins; D001241:Aspirin