Effect of ectopic expression of rat trefoil factor family 3 (intestinal trefoil factor) in the jejunum of transgenic mice.
To further examine the function of the trefoil factor family (TFF), the expression of which is up-regulated at sites of injury, we have produced transgenic mice that chronically express rat TFF3 within the jejunum (using a rat fatty acid-binding protein promoter). The expression of rat TFF3 was limited to the villi of the jejunum and had no effect on base-line morphology. Rat TFF3 expression did result, however, in a reduced sensitivity to indomethacin (85 mg/kg subcutaneously), which only caused a 29% reduction in villus height in transgenics versus 51% reduction in controls (p < 0.01). Indomethacin increased initial intestinal epithelial cell proliferation and migration, but the presence of rat TFF3 caused no additional change in proliferation (bromodeoxyuridine), cell migration ([(3)H]thymidine and bromodeoxyuridine), apoptosis (terminal deoxyuridine nucleotidyl nick end labeling), or E-cadherin immunostaining. In vitro studies following changes in resistance of intestinal strips in Ussing chambers (voltage-clamp technique) showed increased base-line resistance in the rat TFF3-expressing region (326 +/- 60 versus 195 +/- 48 ohm.cm(2) in controls, p < 0.05) and reduced the fall in resistance following HCl exposure by about 40% (p < 0.01). Overexpression of TFF3 stabilizes the mucosa against noxious agents, supporting its role in mucosal protection/repair. It may therefore provide a novel approach to the prevention and/or treatment of intestinal ulceration.
Marchbank
T
T
Department of Gastroenterology, Hammersmith Hospital, Imperial College School of Medicine, London W12 0NN, United Kingdom.
Cox
H M
HM
Goodlad
R A
RA
Giraud
A S
AS
Moss
S F
SF
Poulsom
R
R
Wright
N A
NA
Jankowski
J
J
Playford
R J
RJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019677:Artificial Gene Fusion; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D006133:Growth Substances / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014945:Wound Healing
D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D006133:Growth Substances; D009077:Mucins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; C082495:TFF3 protein, human; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D007213:Indomethacin