Skip to main content
SpringerLink
Log in

Gastric mucosal inflammatory responses toHelicobacter pylori lipopolysaccharide: Suppression of caspase-3 and nitric oxide synthase-2 by omeprazole and sucralfate

  • Short Communication
  • Published:
InflammoPharmacology Aims and scope Submit manuscript

Abstract

Aims:Helicobacter pylori lipopolysaccharide is a primary virulence factor responsible for eliciting acute mucosal inflammatory responses associated withH. pylori infection. In this study, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) duringH. pylori lipopolysaccharide-induced acute gastritis, and evaluated the effect of anti-ulcer agents, omeprazole and sucralfate, on this process.

Methods: Rats, pretreated twice daily with omeprazole at 40 mg/kg, sucralfate at 100 mg/kg, or the vehicle, were subjected to intragastric application ofH. pylori lipopolysaccharide at 50 μg/animal, and after 4 additional days on the anti-ulcer drug or vehicle regimen their mucosal tissue was used for histologic assessment, assays of epithelial cells apoptosis, and the measurements of caspase-3 and NOS-2 activities.

Results: In the absence of anti-ulcer agents,H. pylori lipopolysaccharide induced acute reaction characterized by the inflammatory infiltration of the lamina propria, hyperemia, and epithelial hemorrhage. This was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold induction in mucosal expression of NOS-2, and a 5.4-fold increase in caspase-3 activity. Treatment with proton pump inhibitor, omeprazole, produced a 39.6% reduction in the extent of mucosal inflammatory changes elicited byH. pylori lipopolysaccharide and a 75.5% decrease in the epithelial cells apoptosis, while the activity of caspase-3 decreased by 26.8% and that of NOS-2 showed a 46.7% decline. The gastroprotective agent, sucralfate, evoked a 62.3% reduction in the extent of mucosal inflammatory changes caused by the lipopolysaccharide, epithelial cell apoptosis decreased by 85.8%, and NOS-2 showed a 68.2% decline, while the activity of caspase-3 decreased by 39.7%.

Conclusions: Our findings implicate caspase-3 involvement in gastric mucosal inflammatory responses toH. pylori lipopolysaccharide, and point towards participation of NOS-2 in the amplification of the cell death-signaling cascade. We also show that anti-ulcer agents, omeprazole and sucralfate, are capable of suppressing the H. pylori-induced mucosal inflammatory responses by interfering with the events propagated by NOS-2 and caspase-3.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  • Banerjee, S., El-Omar, E., Mowat, A., Ardill, J. E. S., Park, R. H. R., Watson, W., Beattie, A. D. and McColl, E. L. (1996). Sucralfate suppressesHelicobacter pylori infection and reduces gastric acid secretion by 50% in patients with duodenal ulcer,Gastroenterology 110, 717–724.

    Article  PubMed  CAS  Google Scholar 

  • Bayerdorffer, E., Michalke, S. and Mannes, G. A. (1995). Double blind trial of omeprazole and amoxicillin to cureH. pylori infection in patients with duodenal ulcers,Gastroenterology 108, 1412–1417.

    Article  PubMed  CAS  Google Scholar 

  • Brzozowski, J., Konturek, P. C, Sliwowski, Z., Drozdowicz. D., Pajdo, R., Stachura, J., Hahn, E. G. and Konturek, S. J. (1997). Lipopolysaccharideof Helicobacter pylori protects gastric mucosa via generation of nitric oxide,J. Physiol. Pharmacol. 48, 699–717.

    PubMed  CAS  Google Scholar 

  • Chen, C. C, Wang, J. K., Chen, W. C. and Lin, S. B. (1998). Protein kinase Cv mediates lipopolysaccharide-induced nitric-oxide synthase expression in primary astrocytes,J. Biol. Chem. 273, 19424–19430.

    Article  PubMed  CAS  Google Scholar 

  • Choi, K. B., Wong, F., Harlan, J. H., Chaudhary, P. M., Hood, L. and Karsan, A. (1998). Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway,J. Biol. Chem. 273, 20185–20188.

    Article  PubMed  CAS  Google Scholar 

  • El-Omar, E. M., Oien, K., EI-Nujumi, A., Gillen, D., Wirz, A., Dahill, S., Williams, C, Ardill, J. E. S. and McColl K. E. L. (1997).Helicobacter pylori infection and chronic gastric hypersecretion,Gastroenterology 113, 15–24.

    Article  PubMed  CAS  Google Scholar 

  • Feinstein, D. L., Galea, E., Aquino, D. A., Li, G. C, Xu, H. and Reis, D. J. (1996). Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkB activation,J. Biol. Chem. 271, 17724- 17732.

    Article  PubMed  CAS  Google Scholar 

  • Gabryelewicz, A. (1996). Critical evaluation of the treatment of peptic ulcer disease associated withHelicobacter pylori infection,J. Physiol. Pharmacol. 47, 51–58.

    PubMed  CAS  Google Scholar 

  • Galanos, C, Luderlitz, O. and Westphal, O. (1969). A new method for the extraction of R lipopolysaccharide,Eur. J. Biochem. 9, 245–249.

    Article  PubMed  CAS  Google Scholar 

  • Graham, D. Y., Lew, G. M. and Leckago, J. (1993). Antral G-cell number inHelicobacter pylori infection: effect ofH. pylori eradication,Gastroenterology 104, 1655- 1660.

    PubMed  CAS  Google Scholar 

  • Green, D. R. and Reed, J. C. (1998). Mitochondria and apoptosis,Science 281, 1309–1312.

    Article  PubMed  CAS  Google Scholar 

  • Harris, P. R., Mobley, H. L. T., Perez-Perez, G. I., Blaser, M. J. and Smith, P. D. (1996).Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production,Gastroenterology 111, 419–425.

    Article  PubMed  CAS  Google Scholar 

  • Humke, E. W., Ni, J. and Dixit, V. M. (1998). ERICE, a novel FLICE-activatable caspase,J. Biol. Chem. 273, 15702–15707.

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y. M., Kim, T. H., Seol, D. W., Talanian, R. V. and Billiar, T. R. (1998). Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bc1-2 cleavage and cytochrome c release,J. Biol. Chem. 273, 31437–31441.

    Article  PubMed  CAS  Google Scholar 

  • Kim, C. Y, Jung, H. C, Kim, J. M., Song, I. S. and Kim, C. Y. (1998). Interleukin-8 expression by human neutrophils activated byHelicobacter pylori soluble protein,Scand. J. Gastroenterol. 33, 1249–1255.

    Article  PubMed  CAS  Google Scholar 

  • Kumar, S. and Colussi, P. A. (1999). Prodomains-adaptors-oligimerization: the pursuit of caspase activation in apoptosis,TIBS 24, 1–4.

    PubMed  CAS  Google Scholar 

  • Mannick, J. B., Miao, Y. Q. and Stamler, J. S. (1997). Nitric oxide inhibits Fas-induced apoptosis,J. Biol. Chem. 272, 24 125–24 128.

    Article  CAS  Google Scholar 

  • McGowan, C. C, Cover, T. L. and Blaser, M. J. (1994). The proton pump inhibitor omeprazole inhibits acid survival ofHelicobacter pylori by a urease-independent mechanism,Gastroenterology 107, 738–743.

    PubMed  CAS  Google Scholar 

  • Michida, T., Kawano, S., Masuda, E., Kobayashi, I., Nishimura, Y, Tsujii, M., Takei, Y, Tsuji, S., Nagano, K., Fusamoto, H., Kamada, T. and Sugimoto, T. (1997). Endothclin-1 in the gastric mucosa in stress ulcers of critically ill patients,Am. J. Gastroenterol. 92, 1177–1181.

    PubMed  CAS  Google Scholar 

  • Moss, S. F., Legon, S., Davies, J. and Calam, J. (1994). Cylokine gene expression inHellcobacter pylori associated gastritis,Gut 35, 1567–1570.

    Article  PubMed  CAS  Google Scholar 

  • Moss, S. R, Calam, J., Agarawal, B., Wang, S. and Holl, P. R. (1996). Induction of gastric epithelial apopiosis byHelicobacter pylori, Gut 38, 498–501.

    Article  PubMed  CAS  Google Scholar 

  • Mustafa, S. B. and Olson M. S. (1998). Expression of nitric-oxide synthase in rat Kupffer cells is regulated by cAMP,J. Biol. Chem. 273, 5073–5080.

    Article  PubMed  CAS  Google Scholar 

  • National Institutes of Health, Office of the Director (1994). NIH Consensus Statement:Helicobacter pylori in peptic ulcer disease,JAMA 272, 65–69.

    Article  Google Scholar 

  • O’Connell, M. A., Bennett, B. L., Mercurio, F., Manning, A. M. and Mackman, N. (1998). Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells,J. Biol. Chem. 273, 30410–30414.

    Article  PubMed  CAS  Google Scholar 

  • Olbe, L., Hamlet, A., Dalenback, J. and Fandriks, L. (1996). A mechanism by whichHelicobacter pylori infection of the antrum contributes to the development of duodenal ulcer,Gastroenterology 110, 1386–1394.

    Article  PubMed  CAS  Google Scholar 

  • Pahan, K., Sheikh, F. G., Khan, M., Namboodiri, A. M. S. and Singh, I. (1998). Sphingomyclinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes,J. Biol. Chem. 273, 2591–2600.

    Article  PubMed  CAS  Google Scholar 

  • Piotrowski, J., Majka, J., Slomiany, A. and Slomiany, B. L. (1995).Helicobacter pylori lipopolysaccharide inhibition of gastric mucosal somatostatin receptor,Biochem. Mol. Biol. Int. 36, 491–498.

    PubMed  CAS  Google Scholar 

  • Piotrowski, J., Piotrowski, E., Skrodzka, D., Slomiany, A. and Slomiany, B. L. (1997). Induction of acute gastritis and epithelial apoptosis byHelicobacler pylori lipopolysaccharide,Scand. J. Gastroenterol. 32, 203–211.

    Article  PubMed  CAS  Google Scholar 

  • Piotrowski, J. (1998). Lipopolysaccharide a virulence factor ofHelicobacter pylori: effect of antiulcer agents,J. Physiol. Pharmacol. 49, 3–24.

    PubMed  CAS  Google Scholar 

  • Pounder, R. E. (1997). New developments inHelicobacter pylori eradication therapy,Scand. J. Gastroenterol. 32 (Suppl. 223), 43–45.

    Google Scholar 

  • Price, A. B. (1991). Sydney system: histological division,J. Gastroenterol. Hepatol. 6, 209–222.

    Article  PubMed  CAS  Google Scholar 

  • Rauws E. A. J., Langenberg, W., Houthoff, H., Zanen, M. C. and Tytgat, G. N. J. (1988).Campylobacter pylori-associated chronic active antral gastritis: a prospective study of its prevalence and the effect of antibacterial and antiulcer treatment,Gastroenterology 94, 33–40.

    PubMed  CAS  Google Scholar 

  • Rune, S. J. (1996). Historyof Helicobacter infection,Scand. J. Gastroenterol. 31 (Suppl. 214), 2–4.

    Article  Google Scholar 

  • Salvascn, G. S. and Dixit, V. M. (1997). Caspascs: intracellular signaling by proteolysis,Cell 91, 443–446.

    Article  Google Scholar 

  • Sekkai, D., Aillet, R., Israel, N. and Lepoivre, M. (1998). Inhibition of NFkB and HIV-1 long terminal repeat transcriptional activation by inducible nitric oxide synthase-2 activity,J. Biol. Chem. 273, 3895–3900.

    Article  PubMed  CAS  Google Scholar 

  • Slomiany, B. L., Piotrowski, J. and Slomiany, A. (1997a). Suppression ofHelicobacter pylori urease activity by sucralfate and sulglycolide,Biochem. Mol. Biol. Int. 42, 155–161.

    PubMed  CAS  Google Scholar 

  • Slomiany, B. L., Piotrowski, J. and Slomiany, A. (1997b).Anti-Helicobacter pylori activities of ebrotidine,Arzniem Forsch. Drug Res. 47, 475–482.

    CAS  Google Scholar 

  • Slomiany, B. L., Piotrowski, J. and Slomiany, A. (1998a). Induction of caspase-3 and nitric oxide synthase-2 during gastric mucosal inflammatory reaction toHelicobacter pylori lipopolysaccharide,Biochem. Mol. Biol Int. 46, 1063–1070.

    PubMed  CAS  Google Scholar 

  • Slomiany, B. L., Piotrowski, J. and Slomiany, A. (1998b). Effect of sucralfate on gastric mucosal inflammatory responses induced byHelicobacter pylori lipopolysaccharide,Scand. J. Gastroenterol. 33, 916–922.

    Article  PubMed  CAS  Google Scholar 

  • Slomiany, B. L., Piotrowski, J. and Slomiany, A. (1998c). Effect of sulglycolide on the apoplotic processes associated with indomethacin-induced gastric mucosal injury,Inflammopharmacol. 6, 243–253.

    Article  CAS  Google Scholar 

  • Stolte M. and Edit S. (1996).Helicobacter pylori and the evolution of gastritis,Scand. J. Gastroenterol. 31 (Suppl. 214), 13–16.

    Article  Google Scholar 

  • Thornberry, N. A. and Lazebnik, Y. (1998). Caspases: enemies within,Science 281, 1312–1316.

    Article  PubMed  CAS  Google Scholar 

  • Unge, P. (1996). Review ofHelicobacter pylori eradication regimens,Scand. J. Gastroenterol. 31 (Suppl. 215), 74–81.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Center, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, 07103-2400, Newark, NJ, USA

    B. L. Slomiany, J. Piotrowski & A. Slomiany

Authors
  1. B. L. Slomiany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Piotrowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Slomiany
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. L. Slomiany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Slomiany, B.L., Piotrowski, J. & Slomiany, A. Gastric mucosal inflammatory responses toHelicobacter pylori lipopolysaccharide: Suppression of caspase-3 and nitric oxide synthase-2 by omeprazole and sucralfate. Inflammopharmacol 7, 163–177 (1999). https://doi.org/10.1007/BF02918388

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02918388

Key words

Search

Navigation