- Email: [email protected]
Genetic dissection of the secretory machinery in the stomach
606
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5. Harrison SA, Di Bisceglie AM. Advances in the understanding and treatment of nonalcoholic fatty liver disease. Drugs 2003;63: 2379 –2394. 6. Lawson DH, Gray JMB, McKillop C, Clarke J, Lee FD, Patrick RS. Diabetes mellitus and primary hepatocellular carcinoma. Q J Med 1986;234:945–955. 7. La Vecchia C, Negri E, DeCarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 1997;73:204 – 207. 8. Adami H-O, Chow W-H, Nyren O, Berne C, Linet MS, Ekbom A, Wolk A, McLaughlin JK, Fraumeni JF. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996;88:1472–1477. 9. El-Serag H, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001;96:2462–2467. 10. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460 – 468. 11. Brunt EM, Tiniakos DG. Steatosis, steaohepatitis: review of effects on chronic hepatitis C. Curr Hepatitis Rep 2002;1:38 – 44.
12. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-␥ ligand rosiglitazone. Hepatology 2003; 38:1008 –1017. 13. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750. 14. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults. N Eng J Med 2003;348:1625–1638. 15. Balkau B, Kahn HS, Courbon D, Eschwege E, Ducimetiere P. Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites. Diabetes Care 2001;24:843– 849.
Address request for reprints to: Adrian M. Di Bisceglie, M.D., Division of Gastroenterology and Hepatology, Saint Louis University, 3635 Vista Avenue, St. Louis, Missouri 63110. e-mail: [email protected]. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2003.1.018
Genetic Dissection of the Secretory Machinery in the Stomach See article on page 476.
astric acid secretion from parietal cells is under the regulatory control of the enteric nervous system (ENS), the central nervous system (CNS), and a complex network of neuroendocrine cells acting in an auto- or paracrine manner.1,2 Almost all regulatory pathways converge at two anatomical and functional entities that are crucial for the process of acid secretion: the G cell localized in the antrum as the source of gastrin, the single most important hormonal stimulator of acid output, and the parietal cell of the fundic mucosa as the source of hydrochloric acid itself. It is in this respect that Chen et al. expedite the understanding of these complex events through their elegant study in two strains of genetically engineered animals with targeted disruption of either the gastrin (GAS⫺/⫺) or both gastrin and CCK (GAS⫺/⫺/CCK-/-) genes, because these models integrate the important elements involved in the regulation of acid secretion at the central, peripheral, and cellular level.3 Acid secretion was measured in wild-type (WT), GAS⫺/⫺, and GAS⫺/⫺/CCK⫺/⫺ mice after ligation of the pylorus, and an extensive analysis of the gastric mucosal gene expression, including a detailed picture of the architecture of the gastric glands, was obtained. Targeted disruption of the gastrin gene or both gastrin and CCK genes resulted in functional inactivity of enterochromaf-
G
fin-like (ECL) cells. Parietal cell numbers and H⫹/K⫹– adenosine triphosphatase messenger RNA (mRNA) expression were reduced in both mutant animal strains, although the GAS⫺/⫺/CCK⫺/⫺ mice displayed more active parietal cells and higher acid output than GAS⫺/⫺ mice. The acid response to histamine in GAS⫺/⫺/ CCK⫺/⫺ mice was unchanged, whereas that to gastrin was diminished but could be restored by infusion of gastrin using osmotic minipumps. Oxyntic D cell density was the same in both mutant strains, but D cells were more active in GAS⫺/⫺mice than in GAS⫺/⫺/ CCK⫺/⫺ mice. CCK infusion in GAS⫺/⫺/CCK⫺/⫺ mice raised the somatostatin mRNA level and inhibited acid secretion to the level seen in GAS⫺/⫺ mice. Vagotomy and atropine abolished acid secretion in all 3 groups of mice. Regulation of gastrin release plays a crucial role in the physiological and pathophysiological control of gastric acid secretion. Gastrin is the principal mediator of foodstimulated gastric acid secretion, responsible for at least 50% of the postprandial phase of acid release.4 Another important action of gastrin is the stimulation of mucosal growth in the stomach that results in hyperplasia of the ECL5 and parietal cells.6 The importance of gastrin for the regulation of acid secretion in acid-related pathophysiology was fully acknowledged only recently when it was recognized that Helicobacter pylori–associated antrum gastritis produces hypergastrinemia by disinhibition of gastrin release and thereby contributes to hypersecretion
February 2004
of acid in H. pylori–associated gastritis and duodenal ulcer disease.7,8 The gastrointestinal hormone cholecystokinin (CCK) is released into the circulation from intestinal I cells in response to ingestion of nutrients such as fat and protein9 to stimulate postprandial gallbladder contraction and—at least partially—pancreatic enzyme secretion.10,11 Although gastrin has been identified as a key peptidergic stimulus of acid secretion in response to a meal in most species through direct activation of CCK2 receptors on parietal cells and through release of histamine from ECL cells, the role of the structurally related peptide CCK in the peripheral regulation of acid secretion still is a matter of debate.1,12 The structural similarity of CCK and gastrin and their property to share high affinity for CCK2 receptors suggest that both hormones may stimulate gastric acid secretion.13 However, infusion of CCK in vivo does not result in a potent stimulation of acid secretion in several species, although CCK and gastrin equipotently induce 14C-aminopyrine accumulation, which is an excellent marker for acid secretion in collagenase-dispersed parietal cells from dog14 and rabbit15 in vitro. In vitro studies in isolated canine fundic D cells addressed this discrepancy and postulated that CCK would act preferably via CCK1 receptors to trigger somatostatin release.16,17 The CCKinduced release of somatostatin was postulated to exhibit a tonic inhibition of parietal cells, ECL cells, and gastrinproducing G cells. This concept was further substantiated in humans in vivo by demonstrating that CCK acts as a negative regulator of gastric acid secretion and postprandial release of gastrin.18 Individuals receiving intravenous infusions of CCK resulting in physiological or supraphysiological postprandial serum concentrations had little or no increase of gastric acid secretion. Simultaneous infusion of CCK and the selective CCK1 receptor antagonist loxiglumide converted CCK into a powerful acid secretagogue and yielded in a near maximal response. Conversely, gastrin-induced acid secretion was potently antagonized by coinfusion of gastrin and CCK, suggesting two antagonistic modes or sites of action by alternate recognition of CCK receptor subtypes.18 The cellular targets of CCK and gastrin were eventually visualized in human gastric mucosa at the mRNA and protein levels, revealing expression of CCK1 receptor mRNA and protein in somatostatin-producing D cells.19 Given the functional and morphological evidence of CCK to act preferentially on D cells via CCK1 receptors to release somatostatin, the study by Chen et al. convincingly demonstrates that targeted disruption of the CCK
EDITORIALS
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gene restores impaired acid secretion caused by functional inactivation of the gastrin gene.3 Some important details of the investigation deserve further acknowledgement. First, gastrin-deficient mice have severely impaired parietal cell function with markedly decreased basal acid secretion, resulting in hypochlorhydria as previously reported.20 Part of the impaired acid output may be attributed to the functional loss of ECL cells and their failure to secrete histamine. GAS⫺/⫺ mice also fail to secrete acid upon stimulation with carbachol, a muscarinic type 3 receptor agonist, histamine, or short-term treatment with gastrin, suggesting general acid secreting defects. It was unexpected that the GAS⫺/⫺/CCK⫺/⫺ mice had a high percentage of active parietal cells with a maintained ability to respond with acid secretion to vagal excitation (by pylorus ligation) and to a histamine challenge. Hence, the reduced acid secretion in the GAS⫺/⫺ mice and the restoration of acid secretion in the GAS⫺/⫺/CCK⫺/⫺ mice indicates that CCK plays a significant role as an inhibitor of parietal cells via the CCK-somatostatin pathway. Conceivably, CCK activates CCK1 receptors on D cells in the oxyntic mucosa, mobilizing somatostatin to inhibit parietal cells (and ECL cells) via somatostatin type 2 receptors. In addition, CCK may act on CCK2 receptors on ECL cells to activate histidine decarboxylase and mobilize histamine (more so in WT mice than in GAS⫺/⫺/CCK⫺/⫺ mice). The net acid output will be determined by the balance between stimulating signals from CCK2 receptors on ECL cells on one hand and histamine type 2 receptors on parietal cells and inhibiting signals from somatostatin type 2 receptors on both parietal cells and ECL cells on the other hand. In the absence of stimulating signals from CCK2 receptors and histamine type 2 receptors and inhibiting signals from somatostatin type 2 receptors, acid secretion will be controlled mainly by the vagal pathway. Second, the cholinergic agonist carbachol was found to stimulate acid secretion in WT mice, while reducing acid secretion in GAS⫺/⫺/CCK⫺/⫺ mice. This paradox suggests that the mechanisms that control acid secretion in WT mice differ from those that control acid secretion in GAS⫺/⫺/CCK⫺/⫺ mice. Although carbachol induces acid secretion from parietal cells, it may cause somatostatin release from D cells. The net acid output from parietal cells would then be determined by the balance between a direct stimulating signal and an indirect inhibitory signal from somatostatin. In WT mice, the stimulating signal was dominant, whereas in GAS⫺/⫺/ CCK⫺/⫺ mice, the inhibitory effect was more apparent.
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ciency by itself is characterized by increased basal, gastrin-, and CCK-stimulated acid secretion. In conclusion, targeted disruption of the gastrin and CCK genes proved invaluable to further dissect the regulatory circuits of the acid secretory machinery to unravel the effects of CCK on gastric acid secretion. WOLFGANG E. SCHMIDT FRANK SCHMITZ Department of Medicine I St. Josef-Hospital Ruhr-University of Bochum School of Medicine Bochum, Germany
References
Figure 1. Gastrin stimulates acid secretion primarily through activation of CCK2 receptors on ECL cells through release of histamine. CCK counterbalances gastrin action through release of somatostatin (SST) from antral or fundic D cells, which inhibit histamine release from ECL cells as well as gastrin release from G cells. Despite its nanomolar affinity for CCK2 receptors on cells representing the positive effector pathway, the net effect of CCK on acid secretion is inhibitory. Functional inactivation of both gastrin and CCK results in normal acid secretion following pylorus ligation, whereas gastrin deficiency alone is characterized by hypochlorhydria.
Third, the analysis of the GAS⫺/⫺/CCK⫺/⫺ mice also demonstrated that although gastrin and CCK belong to the same peptide hormone family and share a receptor (the CCK2 receptor), they interact in a complex manner (Figure 1). Although gastrin is primarily involved in stimulating ECL cells (and parietal cells through release of histamine), CCK may either stimulate (through activation of CCK2 receptors) or inhibit ECL cell and parietal cell function (by activating CCK1 receptors on D cells), depending on the circumstances (Figure 1). With the generation of GAS⫺/⫺/CCK⫺/⫺ mice, this complexity is eliminated, making it possible to explore the vagal pathway that controls parietal cell function. The net effect of CCK on acid secretion is thus inhibitory as now demonstrated in genetically engineered mice lacking functional CCK and gastrin genes, supporting the hypothesis that CCK may act as an “enterogastrone”—a duodenal inhibitor of acid secretion21—to restore acid secretion to the basal state when predigested acidic food enters the duodenum and triggers its release from I cells. This concept is in line with observations in CCK1 receptor– deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats,22 a rat strain with a spontaneous inactivation of the CCK1 receptor gene. CCK1R defi-
1. Schmidt WE, Bojko JB. Regulation of gastric acid secretion. In: Greeley GH, ed. Gastrointestinal endocrinology. Totowa, NJ: Humana Press, 1998:353–391. 2. Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2003; 19:519 –525. 3. Chen D, Zhao CM, Hakanson R, Samuelson LC, Rehfeld JF, Friis-Hansen L. Altered control of gastric acid secretion in gastrincholecystokinin double mutant mice. Gastroenterology 2004; 126:476 – 487. 4. Kovacs TO, Walsh JH, Maxwell V, Wong HC, Azuma T, Katt E. Gastrin is a major mediator of the gastric phase of acid secretion in dogs: proof by monoclonal antibody neutralization. Gastroenterology 1989;97:1406 –1413. 5. Larsson H, Carlsson E, Mattsson H, Lundell L, Sundler F, Sundell G, Wallmark B, Watanabe T, Hakanson R. Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 1986;90:391–399. 6. Crean GP, Marshall MW, Rumsey RD. Parietal cell hyperplasia induced by the administration of pentagastrin (ICI 50,123) to rats. Gastroenterology 1969;57:147–155. 7. Levi S, Beardshall K, Swift I, Foulkes W, Playford R, Ghosh P, Calam J. Antral Helicobacter pylori, hypergastrinaemia, and duodenal ulcers: effect of eradicating the organism. BMJ 1989;299: 1504 –1505. 8. el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681– 691. 9. Liddle RA, Goldfine ID, Williams JA. Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 1984;87:542–549. 10. Schmidt WE, Creutzfeldt W, Schleser A, Choudhury AR, Nustede R, Hocker M, Nitsche R, Sostmann H, Rovati LC, Folsch UR. Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide. Am J Physiol 1991;260:G197– G206. 11. Crawley JN, Corwin RL. Biological actions of cholecystokinin. Peptides 1994;15:731–755. 12. Grossman MI. Regulation of gastric acid secretion. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1984:659 – 672. 13. Wank SA. G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family. Am J Physiol Regul Integr Comp Physiol 1998;274:G607–G613. 14. Soll AH, Amirian DA, Thomas LP, Reedy TJ, Elashoff JD. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984; 73:1434 –1447.
February 2004
15. Roche S, Gusdinar T, Bali JP, Magous R. Relationship between inositol 1,4,5-trisphosphate mass level and [14C]aminopyrine uptake in gastrin-stimulated parietal cells. Mol Cell Endocrinol 1991;77:109 –113. 16. Soll AH, Amirian DA, Park J, Elashoff JD, Yamada T. Cholecystokinin potently releases somatostatin from canine fundic mucosal cells in short-term culture. Am J Physiol 1985;248:G569 –G573. 17. Lloyd KC, Maxwell V, Chuang CN, Wong HC, Soll AH, Walsh JH. Somatostatin is released in response to cholecystokinin by activation of type A CCK receptors. Peptides 1994;15:223–227. 18. Schmidt WE, Schenk S, Nustede R, Holst JJ, Folsch UR, Creutzfeldt W. Cholecystokinin is a negative regulator of gastric acid secretion and postprandial release of gastrin in humans. Gastroenterology 1994;107:1610 –1620. 19. Schmitz F, Goke MN, Otte JM, Schrader H, Reimann B, Kruse ML, Siegel EG, Peters J, Herzig KH, Folsch UR, Schmidt WE. Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa. Regulatory Peptides 2001;102:101–110. 20. Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Green-
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son JK, Owyang C, Rehfeld JF, Samuelson LC. Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol 1998;274: G561–G568. 21. Kosaka T, Lim RKS. On the mechanism of the inhibition of gastric secretion by fat. The role of bile and cholecystokinin. Clin J Physiol 1930;4:213–220. 22. Kanagawa K, Nakamura H, Murata I, Yosikawa I, Otsuki M. Increased gastric acid secretion in cholecystokinin-1 receptordeficient Otsuka Long-Evans Tokushima fatty rats. Scand J Gastroenterol 2002;37:9 –16.
Address requests for reprints to: Wolfgang E. Schmidt, M.D., Ph.D., Department of Medicine I, St. Josef-Hospital, Ruhr-University of Bochum School of Medicine, Gudrunstrasse 56, D-44791 Bochum, Germany. e-mail: [email protected]; fax: (49) 234-509-2309. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2003.12.017
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5. Harrison SA, Di Bisceglie AM. Advances in the understanding and treatment of nonalcoholic fatty liver disease. Drugs 2003;63: 2379 –2394. 6. Lawson DH, Gray JMB, McKillop C, Clarke J, Lee FD, Patrick RS. Diabetes mellitus and primary hepatocellular carcinoma. Q J Med 1986;234:945–955. 7. La Vecchia C, Negri E, DeCarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 1997;73:204 – 207. 8. Adami H-O, Chow W-H, Nyren O, Berne C, Linet MS, Ekbom A, Wolk A, McLaughlin JK, Fraumeni JF. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996;88:1472–1477. 9. El-Serag H, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001;96:2462–2467. 10. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460 – 468. 11. Brunt EM, Tiniakos DG. Steatosis, steaohepatitis: review of effects on chronic hepatitis C. Curr Hepatitis Rep 2002;1:38 – 44.
12. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-␥ ligand rosiglitazone. Hepatology 2003; 38:1008 –1017. 13. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750. 14. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults. N Eng J Med 2003;348:1625–1638. 15. Balkau B, Kahn HS, Courbon D, Eschwege E, Ducimetiere P. Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites. Diabetes Care 2001;24:843– 849.
Address request for reprints to: Adrian M. Di Bisceglie, M.D., Division of Gastroenterology and Hepatology, Saint Louis University, 3635 Vista Avenue, St. Louis, Missouri 63110. e-mail: [email protected]. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2003.1.018
Genetic Dissection of the Secretory Machinery in the Stomach See article on page 476.
astric acid secretion from parietal cells is under the regulatory control of the enteric nervous system (ENS), the central nervous system (CNS), and a complex network of neuroendocrine cells acting in an auto- or paracrine manner.1,2 Almost all regulatory pathways converge at two anatomical and functional entities that are crucial for the process of acid secretion: the G cell localized in the antrum as the source of gastrin, the single most important hormonal stimulator of acid output, and the parietal cell of the fundic mucosa as the source of hydrochloric acid itself. It is in this respect that Chen et al. expedite the understanding of these complex events through their elegant study in two strains of genetically engineered animals with targeted disruption of either the gastrin (GAS⫺/⫺) or both gastrin and CCK (GAS⫺/⫺/CCK-/-) genes, because these models integrate the important elements involved in the regulation of acid secretion at the central, peripheral, and cellular level.3 Acid secretion was measured in wild-type (WT), GAS⫺/⫺, and GAS⫺/⫺/CCK⫺/⫺ mice after ligation of the pylorus, and an extensive analysis of the gastric mucosal gene expression, including a detailed picture of the architecture of the gastric glands, was obtained. Targeted disruption of the gastrin gene or both gastrin and CCK genes resulted in functional inactivity of enterochromaf-
G
fin-like (ECL) cells. Parietal cell numbers and H⫹/K⫹– adenosine triphosphatase messenger RNA (mRNA) expression were reduced in both mutant animal strains, although the GAS⫺/⫺/CCK⫺/⫺ mice displayed more active parietal cells and higher acid output than GAS⫺/⫺ mice. The acid response to histamine in GAS⫺/⫺/ CCK⫺/⫺ mice was unchanged, whereas that to gastrin was diminished but could be restored by infusion of gastrin using osmotic minipumps. Oxyntic D cell density was the same in both mutant strains, but D cells were more active in GAS⫺/⫺mice than in GAS⫺/⫺/ CCK⫺/⫺ mice. CCK infusion in GAS⫺/⫺/CCK⫺/⫺ mice raised the somatostatin mRNA level and inhibited acid secretion to the level seen in GAS⫺/⫺ mice. Vagotomy and atropine abolished acid secretion in all 3 groups of mice. Regulation of gastrin release plays a crucial role in the physiological and pathophysiological control of gastric acid secretion. Gastrin is the principal mediator of foodstimulated gastric acid secretion, responsible for at least 50% of the postprandial phase of acid release.4 Another important action of gastrin is the stimulation of mucosal growth in the stomach that results in hyperplasia of the ECL5 and parietal cells.6 The importance of gastrin for the regulation of acid secretion in acid-related pathophysiology was fully acknowledged only recently when it was recognized that Helicobacter pylori–associated antrum gastritis produces hypergastrinemia by disinhibition of gastrin release and thereby contributes to hypersecretion
February 2004
of acid in H. pylori–associated gastritis and duodenal ulcer disease.7,8 The gastrointestinal hormone cholecystokinin (CCK) is released into the circulation from intestinal I cells in response to ingestion of nutrients such as fat and protein9 to stimulate postprandial gallbladder contraction and—at least partially—pancreatic enzyme secretion.10,11 Although gastrin has been identified as a key peptidergic stimulus of acid secretion in response to a meal in most species through direct activation of CCK2 receptors on parietal cells and through release of histamine from ECL cells, the role of the structurally related peptide CCK in the peripheral regulation of acid secretion still is a matter of debate.1,12 The structural similarity of CCK and gastrin and their property to share high affinity for CCK2 receptors suggest that both hormones may stimulate gastric acid secretion.13 However, infusion of CCK in vivo does not result in a potent stimulation of acid secretion in several species, although CCK and gastrin equipotently induce 14C-aminopyrine accumulation, which is an excellent marker for acid secretion in collagenase-dispersed parietal cells from dog14 and rabbit15 in vitro. In vitro studies in isolated canine fundic D cells addressed this discrepancy and postulated that CCK would act preferably via CCK1 receptors to trigger somatostatin release.16,17 The CCKinduced release of somatostatin was postulated to exhibit a tonic inhibition of parietal cells, ECL cells, and gastrinproducing G cells. This concept was further substantiated in humans in vivo by demonstrating that CCK acts as a negative regulator of gastric acid secretion and postprandial release of gastrin.18 Individuals receiving intravenous infusions of CCK resulting in physiological or supraphysiological postprandial serum concentrations had little or no increase of gastric acid secretion. Simultaneous infusion of CCK and the selective CCK1 receptor antagonist loxiglumide converted CCK into a powerful acid secretagogue and yielded in a near maximal response. Conversely, gastrin-induced acid secretion was potently antagonized by coinfusion of gastrin and CCK, suggesting two antagonistic modes or sites of action by alternate recognition of CCK receptor subtypes.18 The cellular targets of CCK and gastrin were eventually visualized in human gastric mucosa at the mRNA and protein levels, revealing expression of CCK1 receptor mRNA and protein in somatostatin-producing D cells.19 Given the functional and morphological evidence of CCK to act preferentially on D cells via CCK1 receptors to release somatostatin, the study by Chen et al. convincingly demonstrates that targeted disruption of the CCK
EDITORIALS
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gene restores impaired acid secretion caused by functional inactivation of the gastrin gene.3 Some important details of the investigation deserve further acknowledgement. First, gastrin-deficient mice have severely impaired parietal cell function with markedly decreased basal acid secretion, resulting in hypochlorhydria as previously reported.20 Part of the impaired acid output may be attributed to the functional loss of ECL cells and their failure to secrete histamine. GAS⫺/⫺ mice also fail to secrete acid upon stimulation with carbachol, a muscarinic type 3 receptor agonist, histamine, or short-term treatment with gastrin, suggesting general acid secreting defects. It was unexpected that the GAS⫺/⫺/CCK⫺/⫺ mice had a high percentage of active parietal cells with a maintained ability to respond with acid secretion to vagal excitation (by pylorus ligation) and to a histamine challenge. Hence, the reduced acid secretion in the GAS⫺/⫺ mice and the restoration of acid secretion in the GAS⫺/⫺/CCK⫺/⫺ mice indicates that CCK plays a significant role as an inhibitor of parietal cells via the CCK-somatostatin pathway. Conceivably, CCK activates CCK1 receptors on D cells in the oxyntic mucosa, mobilizing somatostatin to inhibit parietal cells (and ECL cells) via somatostatin type 2 receptors. In addition, CCK may act on CCK2 receptors on ECL cells to activate histidine decarboxylase and mobilize histamine (more so in WT mice than in GAS⫺/⫺/CCK⫺/⫺ mice). The net acid output will be determined by the balance between stimulating signals from CCK2 receptors on ECL cells on one hand and histamine type 2 receptors on parietal cells and inhibiting signals from somatostatin type 2 receptors on both parietal cells and ECL cells on the other hand. In the absence of stimulating signals from CCK2 receptors and histamine type 2 receptors and inhibiting signals from somatostatin type 2 receptors, acid secretion will be controlled mainly by the vagal pathway. Second, the cholinergic agonist carbachol was found to stimulate acid secretion in WT mice, while reducing acid secretion in GAS⫺/⫺/CCK⫺/⫺ mice. This paradox suggests that the mechanisms that control acid secretion in WT mice differ from those that control acid secretion in GAS⫺/⫺/CCK⫺/⫺ mice. Although carbachol induces acid secretion from parietal cells, it may cause somatostatin release from D cells. The net acid output from parietal cells would then be determined by the balance between a direct stimulating signal and an indirect inhibitory signal from somatostatin. In WT mice, the stimulating signal was dominant, whereas in GAS⫺/⫺/ CCK⫺/⫺ mice, the inhibitory effect was more apparent.
608
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ciency by itself is characterized by increased basal, gastrin-, and CCK-stimulated acid secretion. In conclusion, targeted disruption of the gastrin and CCK genes proved invaluable to further dissect the regulatory circuits of the acid secretory machinery to unravel the effects of CCK on gastric acid secretion. WOLFGANG E. SCHMIDT FRANK SCHMITZ Department of Medicine I St. Josef-Hospital Ruhr-University of Bochum School of Medicine Bochum, Germany
References
Figure 1. Gastrin stimulates acid secretion primarily through activation of CCK2 receptors on ECL cells through release of histamine. CCK counterbalances gastrin action through release of somatostatin (SST) from antral or fundic D cells, which inhibit histamine release from ECL cells as well as gastrin release from G cells. Despite its nanomolar affinity for CCK2 receptors on cells representing the positive effector pathway, the net effect of CCK on acid secretion is inhibitory. Functional inactivation of both gastrin and CCK results in normal acid secretion following pylorus ligation, whereas gastrin deficiency alone is characterized by hypochlorhydria.
Third, the analysis of the GAS⫺/⫺/CCK⫺/⫺ mice also demonstrated that although gastrin and CCK belong to the same peptide hormone family and share a receptor (the CCK2 receptor), they interact in a complex manner (Figure 1). Although gastrin is primarily involved in stimulating ECL cells (and parietal cells through release of histamine), CCK may either stimulate (through activation of CCK2 receptors) or inhibit ECL cell and parietal cell function (by activating CCK1 receptors on D cells), depending on the circumstances (Figure 1). With the generation of GAS⫺/⫺/CCK⫺/⫺ mice, this complexity is eliminated, making it possible to explore the vagal pathway that controls parietal cell function. The net effect of CCK on acid secretion is thus inhibitory as now demonstrated in genetically engineered mice lacking functional CCK and gastrin genes, supporting the hypothesis that CCK may act as an “enterogastrone”—a duodenal inhibitor of acid secretion21—to restore acid secretion to the basal state when predigested acidic food enters the duodenum and triggers its release from I cells. This concept is in line with observations in CCK1 receptor– deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats,22 a rat strain with a spontaneous inactivation of the CCK1 receptor gene. CCK1R defi-
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Address requests for reprints to: Wolfgang E. Schmidt, M.D., Ph.D., Department of Medicine I, St. Josef-Hospital, Ruhr-University of Bochum School of Medicine, Gudrunstrasse 56, D-44791 Bochum, Germany. e-mail: [email protected]; fax: (49) 234-509-2309. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2003.12.017