Abstract
It remains controversial whether the harmfuleffects of Helicobacter pylori (Hp) and nonsteroidalantiinflammatory drugs (NSAIDs) are additive. We studiedthe effects of Hp (virulent and nonvirulent strains) and NSAIDs, alone or in combination, onapoptosis and proliferation of gastric epithelial cellsin nonulcer dyspepsia (NUD) patients. Forty-four (25Hppositive and 19 Hp-negative) consecutive Chinese NUD patients with rheumatoid arthritis who hadtaken continuously NSAIDs for more than three monthswere recruited for this study. Another 41 (20Hp-positive and 21 Hp-negative) NUD patients not on anyNSAIDs were included as controls. All patientsunderwent a gastroscopy examination and gastricbiopsies. Hp infection was confirmed by CLOtest, anti-HpELISA, and [13C]urea breath test. The CagAstatus was determined by the anti-CagA antibody assay. The degree ofgastritis, apoptosis, and proliferation indices weredetermined with H&E staining, terminal uridinedeoxynucleotidyl nick end-labeling (TUNEL), andproliferating cell nuclear antigen (PCNA) immunostainingmethods, respectively. A significantly higher apoptosiswas observed in subjects who had Hp infection or hadbeen consuming NSAIDs when compared with the controls. Unlike NSAID-treated subjects, patients with Hpinfection were shown to have significantly enhanced cellproliferation. However, the increased apoptosis andproliferation in Hp-positive subjects were reversed by also taking NSAIDs. No correlation was foundbetween apoptosis and proliferation in all the studygroups. There was no association found between CagAexpression or degree of gastritis with cellproliferation or apoptosis. It was demonstrated at thecellular level that NSAIDs could abrogate apoptosis orproliferation effects induced by Hp. Furthermore, thelatter effects appeared not to be influenced by the virulent nature of the Hp strains.
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REFERENCES
Graham DY: The relationship between nonsteroidal anti-inflammatory drug use and peptic ulcer disease. Gastroenterol Clin North Am 19: 171–182, 1990
Goggin PM, Collins DA, Jazrawi RP, Jackson PA, Corbishley CM, Bourke BE, Northfield TC: Prevalence of Helicobacter pyloriinfection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis. Gut 34: 1677–1680, 1993
Walsh JH: Unanswered question about Helicobacter pylori. Aliment Pharmacol Ther 9(suppl 1): 31–37, 1995
Taha AS, Sturrock TD, Russell RI: Mucosal erosions in longterm non-steroidal anti-inflammatory drug users: Predisposition to ulceration and relation to Helicobacter pylori. Gut 36: 334–336, 1995
Hall PA, Coates PJ, Ansari B, Hopwood D: Regulation of cell number in the mammalian gastrointestinal tract: The importance of apoptosis. J Cell Sci 107: 3569–3577, 1994
Que FG, Gores GJ: Cell death by apoptosis: basic concepts and disease relevance for the gastroenterologist. Gastroenterology 110: 1238–1243, 1996
Spyridon L, Akira N, Hiromasa K, Katsutoshi G, Takao M, Yoshiki O, Hideo S, Hisayuki F: The development of the endothelin-1-induced gastric ulcer: time sequence analysis of morphologic changes. Int J Exp Pathol 75: 345–355, 1994
Benedetti A, Mancini R, Marucci L, Paolucci F, Jezequel AM, Orlandi F: Quantitative study of apoptosis in normal rat gastroduodenal mucosa. J Gastroenterol Hepatol 5: 369–374, 1990
Moss SF, Calam J, Agarwal B, Wang S, Holt PR: Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 34: 498–501, 1996
Lynch DAF, Axon ATR: Helicobacter pylori, gastric cancer and gastric epithelial kinetics: A review. Eur J Gastroenterol Hepatol 7(suppl 1): s17–s23, 1995
Panella C, Ierardi E, Polimeno L, Balzano T, Ingrosso M, Amoruso A, Traversa A, Francavilla A: Proliferative activity of gastric epithelium in progressive stage s of Helicobacter pyloriinfection. Dig Dis Sci 41: 1132–1138, 1996
Brenes F, Ruiz B, Correa P, Hunter F, Rhamakrisham T, Fontham E, Shi TY: Helicobacter pyloricauses hyperproliferation of the gastric epithelium: Pre-and post-eradication indices of proliferating cell nuclear antigen. Am J Gastroenterol 88: 1870–1875, 1993
Levi S, Goodlad RA, Lee CY, Walport MJ, Wright NA, Hodgeson HJF: Effects of nonsteroidal anti-inflammatory drugs and misoprostal on gastroduodenal epithelial proliferation in arthritis. Gastroenterology 102: 1605–1611, 1992
Graham DY, Smith JL, Spjut HJ, Torres E: Gastric adaptation: studies in humans during continuous aspirin administration. Gastroenterology 95: 327–333, 1988
Marnett LJ: Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52: 5575–5589, 1992
Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121: 241–246, 1994
Shiff SJ, Qiao L, Tsai LL, Rigas B: Sulindac sulfide, an aspirinlike compound, inhibits proliferation, cause s cell cycle quiescence, and induce apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 96: 491–503, 1995
Shiff SJ, Koutsos MI, Qiao L, Rigas B: Nonsteroidal anti-inflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: Effects on cell cycle and apoptosis. Exp Cell Res 222: 179–188, 1996
O'Morain C, Buckley M: Helicobacter pyloriand dyspepsia. Scand J Gastroenterol 31( suppl)214: 28–30, 1996
Ching CK, Wong BCY, Kwok E, Ong L, Covacci A, Lam SK: Prevalence of CagA-bearing Helicobacter pyloristrains detected by the anti-CagA assay in patients with peptic ulcer disease and in controls. Am J Gastroenterol 91: 949–953, 1996
Gavrieli Y, Sherman Y, Ben-Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119: 493–501, 1992
Yamada K, Yoshitake K, Sato M, Ahnen DJ: Proliferating cell nuclear antigen expression in normal, preneoplastic, and neoplastic colon epithelium of the rat. Gastroenterology 103: 160–167, 1992
Loeb DS, Talley NJ, Ahlquist DA, Carpenter HA, Zinsmeister AR: Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: The role of Helicobacter pylori. Gastroenterology 102: 1899–1905, 1992
Ormand JE, Talley NJ, Carpenter HA, Shorter RG, Conley CR, Wilson WR, DiMagno EP, Zinsmeister AR, Phillips SF: [14C]Urea breath test for diagnosis of Helicobacter pylori. Dig Dis Sci 35: 879–884, 1990
Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ETH, Mera R, Miller MJS, Correa P: Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylorigastritis: Effect of antibiotics and antioxidants. Cancer Res 56: 3238–3243, 1996
Zhu GH, Ching CK, Lam SK, Sheng JZ, Wong TM, Ding SZ: Sialic acid dependent H. pylorilectin as activator of calcium signal in cultured epithelial cells. Gastroenterology 110: A307, 1996
McConkey DJ, Orrenius S: The role of calcium in the regulation of apoptosis. J Leukoc Biol 59: 775–783, 1996
Piotrowski J, Piotrowski E, Skrodzka D, Slomiany A, Slomiany BL: Induction of acute gastritis and epithelial apoptosis by Helicobacter pylorilipopolysaccharide. Scand J Gastroenterol 32: 203–211, 1997
Wong BCY, Zhu GH, Eggo MC, Yuen ST, Chan EYT, Lam SK: Nonsteroidal antiinflammatory drugs (NSAIDs) induces apoptosis in human gastric carcinoma cells. Gastroenterology 112: A683, 1997
Meikrantz W, Schlegel R: Apoptosis and the cell cycle. J Cell Biochem 58: 160–174, 1995
Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK: Helicobacter pyloriinfection and the risk of gastric carcinoma. N Engl J Med 325: 1127–1131, 1991
The Eurogast Study Group: An international association between Helicobacter pyloriinfection and gastric cancer. Lancet 314: 1359–1362, 1993
Fraser AG, Sim R, Sankey EA, Dhillon AP, Pounder RE: Effect of eradication of Helicobacter pylorion gastric epithelial cell proliferation. Aliment Pharmacol Ther 8: 167–173, 1994
Ames BN, Gold LS: Too many rodent carcinogens: Mitogenesis increase s mutagenesis. Science 249: 970–971, 1990
Lipkin M: Biomarkers of increase d susceptibility to gastrointestinal cancer: New application to studies of cancer prevention in human subjects. Cancer Res 48: 235–245, 1988
Sant SM, Cahill RJ, Gilvarry J, O'Morain CA: Do nonsteroidal anti-inflammatory drugs have an e ffect on gastric cell turnover? Aliment Pharmacol Ther 9: 575–579, 1995
Levi S, Goodlad RA, Lee CY, Stamp G, Walport MJ, Wright NA, Hodgson HJF: Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet 336: 840–843, 1990
Emery P, Samon M: Systemic mediators of inflammation. Br J Hosp Med 45: 164–168, 1991
Lunec J: Fre e radicals: Their involvement in disease processes. Ann Clin Biochem 27: 173–182, 1990
Blaser MJ, Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomurn A: Infection with Helicobacter pyloristrains possessing CagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55: 2111–2115, 1995
Peek RM Jr, Moss SF, Tham KT, Perez-Pe rez GI, Wang SB, Miller GG, Atherton JC, Holt PR, Blaser MJ: Helicobacter pyloricagA+ strains and dissociation of gastric epithelial cells proliferation from apoptosis. J Natl Cancer Inst 89: 863–868, 1997
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Zhu, G.H., Yang, X.L., Lai, K.C. et al. Nonsteroidal Antiinflammatory Drugs Could Reverse Helicobacter pylori-Induced Apoptosis and Proliferation in Gastric Epithelial Cells. Dig Dis Sci 43, 1957–1963 (1998). https://doi.org/10.1023/A:1018830408397
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DOI: https://doi.org/10.1023/A:1018830408397