title: Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome.
abstract: Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin beta(3) levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.
authors.affiliation: Washington Univ. School of Medicine, Campus Box 8124, 660 South Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Tang
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Rubin
authors.forename: Marc S
authors.initials: MS
authors.lastname: Levin
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004343:Drug Implants; D020895:Enterocytes / Q000187:drug effects / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008297:Male; D000073718:Pancreatitis-Associated Proteins; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012778:Short Bowel Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D004343:Drug Implants; D016326:Extracellular Matrix Proteins; D053823:Hedgehog Proteins; D000073718:Pancreatitis-Associated Proteins; D047492:Peroxisome Proliferator-Activated Receptors; C000612141:REG3A protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D051153:Wnt Proteins; D051176:beta Catenin; D014212:Tretinoin