Transforming growth factor alpha inhibits secretion of gastric acid.

229

Transforming growth factor a (TGFa) shares with epidermal growth factor (EGF) structural homology (35%), a common cell-surface membrane receptor (TGFa/EGF receptor), and a nearly identical spectrum of biological activity, including inhibition of gastric acid secretion. Herein, we report expression of TGFa mRNA in normal gastric mucosa of the adult guinea pig, rat, and dog. TGFa mRNA was also detected in matched surgically resected gastric mucosa and adjacent gastric carcinoma from 10 patients, and in gastric mucosa adjacent to a benign ulcer from an additional patient. TGFa protein was quantitated by radioimmunoassay and was present in tumor and adjacent mucosa. TGFa/EGF receptor mRNA was also detected in gastric mucosa from all species studied. Localization of TGFa and TGFa/EGF receptor mRNA expression was examined in samples of unfractionated guinea pig gastric mucosa and from chief cell-enriched and parietal cell-enriched fractions. All samples exhibited TGFa and TGFa/EGF receptor expression. The TGFa signal was greatest in the parietal cell fraction (5.8-fold increase), but was also enhanced in the chief cell fraction (1.9-fold increase) relative to the unfractionated gastric mucosa. Like TGFa expression, TGFa/EGF receptor mRNA expression was most intense in the parietal cellenriched fraction (7.8-fold increase), but was also increased in the chief cell-enriched fraction (2.7-fold increase) relative to the unfractionated guinea pig gastric mucosa. We conclude that TGFa and TGFa/EGF receptor genes are expressed in normal adult mammalian gastric mucosa. These findings, when interpreted in light of described actions of TGFa and EGF, provide evidence that local production of TGFa could play an important role in the regulation of acid secretion and mucosal renewal in the stomach.

Section: Discussionmentioning

confidence: 92%

Localization of transforming growth factor alpha and its receptor in gastric mucosal cells. Implications for a regulatory role in acid secretion and mucosal renewal.

Beauchamp¹,

Barnard²,

McCutchen³

et al. 1989

229

“…These include its ability to inhibit gastric acid secretion and to stimulate arachidonate metabolism (7,8). Of relevance to the present studies is the recent demonstration that EGF can serve as a potent constrictive agent for vascular smooth muscle (9,10).…”

Section: Introductionmentioning

confidence: 83%

Evidence for glomerular actions of epidermal growth factor in the rat.

Harris¹,

Hoover²,

Jacobson³

et al. 1988

109

Epidermal growth factor (EGF), an endogenous mitogenic peptide, has recently been shown to be a potent vasoconstrictor of vascular smooth muscle. In view of its potential role in proliferative and infl tory renal glomerular diseases, we examined the effects of EGF both on cultured rat mesangial cells and on in vivo glomerular hemodynamics. Mesangial cells possess specific, saturable EGF receptors of differing affinities, with Kd's of 0.1 and 1.7 nM, respectively. EGF produced a rapid increase in intracellular pH of 0.12±0.01 pH U, which was sodium dependent and amiloride inhibitable. The addition of EGF to mesangial cells cultured on either glass or dimethylpolysiloxane substratum induced reproducible cell contraction.Intrarenal EGF infusion did not affect systemic blood pressure or hematocrit but reversibly decreased GFR and renal blood flow from 4.19±0.33 to 3.33±0.26 and from 1.17±0.09 to 0.69±0.07 ml/min, respectively. Glomerular micropuncture confirmed decreases in single nephron plasma flow and in single nephron GFR (from 142±9 to 98±8 and from 51.6±11.7 to 28.5±3.5 nl/min, respectively) which were due to significant increases in both pre-and postglomerular arteriolar resistances (from 1.97±0.31 to 2.65±0.36 and from 1.19±0.11 to 2.00±0.15 10'°dyn. s cm-' respectively) and to a significant decrease in the ultrafiltration coefficient, Kf, which fell from 0.100±0.019 to 0.031±0.007 nl/(s mmHg).These studies demonstrate that mesangial cells possess specific receptors for EGF, and exposure of these cells to physiologic concentrations of EGF results in an in vitro functional response characterized by activation of Na+/H+ exchange and by resultant intracellular alkalinization, as well as by cell contraction. EGF administration in vivo significantly reduces the glomerular capillary ultrafiltration coefficient, Kf, which, in combination with EGF-induced constriction of both preglomerular and postglomerular arterioles, results in acute major reductions in the rates of glomerular filtration and perfusion.

“…Volume 90, September 1992, 1161-1167 inhibitor of gastric acid secretion ( 12), and EGF can stimulate gastric mucosal growth in rodents ( 13,14).…”

Section: Introductionmentioning

confidence: 99%

Hypertrophic gastropathy resembling Ménétrier's disease in transgenic mice overexpressing transforming growth factor alpha in the stomach.

Takagi¹,

Jhappan²,

Sharp³

et al. 1992

136

Transforming growth factor a (TGFa) is thought to participate in the normal and pathologic processes of numerous tissues, including the gastric mucosa. To explore its role in vivo, transgenic mice were generated overexpressing TGFa in the stomach. TGFa induced dramatic structural and functional lesions of the glandular stomach that were similar to Menetrier's disease in humans. Transgenic mice developed severe adenomatous hyperplasia that resulted in a striking nodular thickening or hypertrophy of the gastric mucosa. Secretions obtained from affected stomachs contained no detectable gastric acid, suggesting that parietal cell function had been greatly impaired. These findings demonstrate that overproduction of TGFa can stimulate cellular proliferation, suppress acid secretion, and perturb organogenesis ofthe stomach oftransgenic mice. Moreover, TGFa may contribute to the pathogenesis of related human hypertrophic gastropathies, such as Menetrier's disease. (J. Clin. Invest. 1992.90:1161-1167