TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury
James J. Farrell, Douglas Taupin, Theodore J. Koh, Duan Chen, Chun-Mei Zhao, Daniel K. Podolsky, Timothy C. Wang
James J. Farrell, Douglas Taupin, Theodore J. Koh, Duan Chen, Chun-Mei Zhao, Daniel K. Podolsky, Timothy C. Wang
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TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury

Abstract

Trefoil factor family 2 (TFF2), also known as spasmolytic polypeptide, is a member of the trefoil family of peptides and is expressed primarily in the mucous neck cells of the gastric mucosa. To study the physiologic role of TFF2, we have generated TFF2-deficient mice through targeted gene disruption. Homozygous mutant mice were viable and fertile without obvious gastrointestinal abnormalities. However, quantitative measurements revealed a significant decrease in gastric mucosal thickness and in gastric mucosal proliferation rates. In addition, there was a twofold increase in activated parietal cells resulting in a twofold increase in basal and stimulated gastric acid output and an undetectable serum gastrin level. The TFF2-deficient mice also showed a significant increase in the degree of gastric ulceration after administration of indomethacin. Taken together, these results suggest a physiologic role for TFF2 to promote mucosal healing through the stimulation of proliferation and downregulation of gastric acid secretion.

Authors

James J. Farrell, Douglas Taupin, Theodore J. Koh, Duan Chen, Chun-Mei Zhao, Daniel K. Podolsky, Timothy C. Wang

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Increased parietal cell activation and acid secretion in TFF2-deficient ...
Increased parietal cell activation and acid secretion in TFF2-deficient mice. (a) Increased basal gastric acid secretion in fed TFF2-deficient mice. Basal gastric acid output was calculated in the resting state of fed wild-type and TFF2-deficient mice and expressed as μEquivalent of H+. Results are expressed as mean acid output ± SEM and represent data from analysis of eight wild-type mice and eight TFF2-deficient mice. (P < 0.05). (b) Increased stimulated gastric acid secretion in TFF2-deficient mice. Stimulated gastric acid output was calculated in wild-type and TFF2-deficient mice after administration of bethanechol (2.5 mg/kg intraperitoneally) and expressed as μEquivalent of H+. Results are expressed as mean acid output ± SEM and represent data from analysis of eight wild-type mice and eight TFF2-deficient mice. (P < 0.04). (c) Parietal cell activation. Random low-powered electron micrographs were obtained (×3,000). Both activated and inactivated parietal cells are identified by their unique ultrastructure. Activated parietal cells are defined as cells having an expansion of their secretory canaliculi. Inactive parietal cell (left panel). Activated parietal cell (right panel). (d) Increased parietal cell activation in fed TFF2-deficient mice compared with wild-type mice under resting conditions. Results are expressed number of activated parietal cells as a percentage of total parietal cells counted ± SE of four mice. (P < 0.02). (e) No change in HB-EGF protein expression. Western blot analysis of stomach protein (50 μg total protein per lane) shows no difference in expression of HB-EGF protein in TFF2-deficient (–/–) compared with wild-type mice (+/+). Purified human HB-EGF was used as a positive control (not shown). M, size marker; MW, molecular weight.