Elevated gaseous luminal nitric oxide and circulating IL-8 as features of Helicobacter pylori-induced gastric inflammation

  • Hiwa K. Saaed Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden https://orcid.org/0000-0003-1078-514X
  • Lisa Chiggiato Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden https://orcid.org/0000-0003-2784-8880
  • Dominic-Luc Webb Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden https://orcid.org/0000-0002-6979-9194
  • Ann-Sofie Rehnberg Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden
  • Carlos A. Rubio Department of Pathology, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden https://orcid.org/0000-0003-3879-5729
  • Ragnar Befrits Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden
  • Per M. Hellström Department of Medical Sciences, Gastroenterology and Hepatology Unit, Uppsala University, Uppsala, Sweden https://orcid.org/0000-0001-8428-0772
Keywords: Nitric oxide, Helicobacter pylori, inflammation, cytokines, biomarkers

Abstract

Background: Gastric nitric oxide (NO) production in response to Helicobacter pylori via inducible nitric oxide synthase (iNOS) is suggested as a biomarker of inflammation and cytotoxicity. The aim of this study was to investigate relationships between gastric [NO], immunological biomarkers and histopathology.

Materials and methods: Esophagogastroduodenoscopy was done in 96 dyspepsia patients. Luminal [NO] was measured by chemiluminescence. Biopsies were taken from gastric antrum and corpus for culture and histopathology. H. pylori IgG was detected by immunoblot assay. Biobanked plasma from 76 dyspepsia patients (11 H. pylori positives) was analyzed for 39 cytokines by multiplexed ELISA.

ResultsH. pylori-positive patients had higher [NO] (336 ± 26 ppb, mean ± 95% CI, n = 77) than H. pylori-negative patients (128 ± 47 ppb, n = 19) (P < 0.0001). Histopathological changes were found in 99% of H. pylori-positive and 37% of H. pylori-negative patients. Histopathological concordance was 78–100% between corpus and antrum. Correlations were found between gastric [NO] and severity of acute, but not chronic, inflammation. Plasma IL-8 (increased in H. pylori positives) had greatest difference between positive and negative groups, with eotaxin, MIP-1β, MCP-4, VEGF-A, and VEGF-C also higher (P < 0.004 to P < 0.032). Diagnostic odds ratios using 75% cut-off concentration were 7.53 for IL-8, 1.15 for CRP, and 2.88 for gastric NO.

Conclusions: Of the parameters tested, increased gastric [NO] and circulating IL-8 align most consistently and selectively in H. pylori-infected patients. Severity of mucosal inflammatory changes is proportional to luminal [NO], which might be tied to IL-8 production. It is proposed that IL-8 be further investigated as a blood biomarker of treatment outcomes.

Downloads

Download data is not yet available.

References


  1. 8116_F000Testerman TL, McGee DJ, Mobley HLT. Adherence and colonization. In: Mobley HL, Mendz GL, Hazell SL, directeurs. Helicobacter pylori: physiology and genetics. [En ligne]. Washington, DC: ASM Press; 2001. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2437/ [cited 15 January 2021].

  2. 8116_F000Bugaytsova JA, Chernov YA, Gideonsson P, Björnham O, Henriksson S, Mendez M, et al. Adaption of Helicobacter pylori to chronic infection and gastric disease by pH-responsive BabA-mediated adherence. Cell Host Microbe 2017;21:376–89. doi: 10.1016/j.chom.2017.02.013

  3. 8116_F000Nielsen H, Andersen LP. Activation of human phagocyte oxidative metabolism by Helicobacter pylori. Gastroenterology 1992;103:1747–53. doi: 10.1016/0016-5085(92)91430-C

  4. 8116_F000Dixon MF. Pathology of gastritis and peptic ulceration. In: Mobley HL, Mendz GL, Hazell SL, directeurs. Helicobacter pylori: physiology and genetics. [En ligne]. Washington, DC: ASM Press; 2001. Available from: http://www.ncbi.nlm.nih.gov/books/NBK2461/ [cited 15 January 2021].

  5. 8116_F000Gobert AP, Wilson KT. The immune battle against Helicobacter pylori infection: NO offense. Trends Microbiol 2016;24:366–76. doi: 10.1016/j.tim.2016.02.005

  6. 8116_F000Harris PR, Weber HC, Wilcox CM, Jensen RT, Smith PD. Cytokine gene profile in gastric mucosa in Helicobacter pylori infection and Zollinger-Ellison syndrome. Am J Gastroenterol 2002;97:312–18. doi: 10.1111/j.1572-0241.2002.05463.x

  7. 8116_F000Khaiboullina SF, Abdulkhakov S, Khalikova A, Safina D, Martynova EV, Davidyuk Y, et al. Serum cytokine signature that discriminates Helicobacter pylori positive and negative juvenile Gastroduodenitis. Front Microbiol 2016;7:1916. doi: 10.3389/fmicb.2016.01916

  8. 8116_F000Kim TJ, Pyo JH, Lee H, Baek SY, Ahn SH, Min YW, et al. Lack of association between Helicobacter pylori infection and various markers of systemic inflammation in asymptomatic adults. Korean J Gastroenterol 2018;72:21–7. doi: 10.4166/kjg.2018.72.1.21

  9. 8116_F000Tindberg Y, Bengtsson C, Bergstrom M, Granstrom M. The accuracy of serologic diagnosis of Helicobacter pylori infection in school-aged children of mixed ethnicity. Helicobacter 2001;6:24–30. doi: 10.1046/j.1523-5378.2001.00005.x

  10. 8116_F000Hoang TTH, Wheeldon T-U, Bengtsson C, Phung DC, Sorberg M, Granstrom M. Enzyme-linked immunosorbent assay for Helicobacter pylori needs adjustment for the population investigated. J Clin Microbiol 2004;42:627–30. doi: 10.1128/JCM.42.2.627-630.2004

  11. 8116_F000Sörberg M, Engstrand L, Ström M, Jönsson K-Å, Jörbeck H, Granström M. The diagnostic value of enzyme immunoassay and immunoblot in monitoring eradication of Helicobacter pylori. Scand J Infect Dis 1997;29:147–51. doi: 10.3109/00365549709035875

  12. 8116_F000Shiotani A, Iishi H, Kumamoto M, Nakae Y. Helicobacter pylori infection and increased nitrite synthesis in the stomach. Dig Liver Dis 2004;36:327–32. doi: 10.1016/j.dld.2003.11.029

  13. 8116_F000Parikh R, Mathai A, Parikh S, Chandra Sekhar G, Thomas R. Understanding and using sensitivity, specificity and predictive values. Indian J Ophthalmol 2008;56:45–50.

  14. 8116_F000Kai H, Ito M, Kitadai Y, Tanaka S, Haruma K, Chayama K. Chronic gastritis with expression of inducible nitric oxide synthase is associated with high expression of interleukin-6 and hypergastrinaemia. Aliment Pharmacol Ther 2004;19:1309–14. doi: 10.1111/j.1365-2036.​2004.01965.x

  15. 8116_F000Von Bothmer C, Edebo A, Lönroth H, Olbe L, Pettersson A, Fändriks L. Helicobacter pylori infection inhibits antral mucosal nitric oxide production in humans. Scand J Gastroenterol 2002;37:404–8. doi: 10.1080/003655202317316024

  16. 8116_F000Webb D-L, Rudholm-Feldreich T, Gillberg L, Halim MdA, Theodorsson E, Sanger GJ, et al. The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression. Naunyn Schmiedebergs Arch Pharmacol 2013;386:41–9. doi: 10.1007/s00210-012-0812-5

  17. 8116_F000Calatayud S, Barrachina D, Esplugues JV. Nitric oxide: relation to integrity, injury, and healing of the gastric mucosa. Microsc Res Tech 2001;53:325–35. doi: 10.1002/jemt.1100

  18. 8116_F000Kim JM, Kim JS, Jung HC, Song IS, Kim CY. Up-regulation of inducible nitric oxide synthase and nitric oxide in Helicobacter pylori-infected human gastric epithelial cells: possible role of interferon-gamma in polarized nitric oxide secretion. Helicobacter 2002;7:116–28. doi: 10.1046/j.1083-4389.2002.00068.x

  19. 8116_F000Tsuji S, Kawano S, Tsujii M, Takei Y, Tanaka M, Sawaoka H, et al. Helicobacter pylori extract stimulates inflammatory nitric oxide production. Cancer Lett 1996;108(2):195–200. doi: 10.1016/S0304-3835(96)04410-2

  20. 8116_F000Rubio CA. My approach to reporting a gastric biopsy. J Clin Pathol 2006;60:160–6. doi: 10.1136/jcp.2006.039008

  21. 8116_F000Herulf M, Ljung T, Hellström P. Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method. Scand J Gastroenterol 1998;33:164–9. doi: 10.1080/00365529850166897

  22. 8116_F000Herulf M, Blomquist L, Ljung T. Increased rectal nitric oxide in coeliac disease after local challenge with gluten. Scand J Gastroenterol 2001;36:169–73. doi: 10.1080/00365520118744

  23. 8116_F000Konturek PC, Konturek JW, Konturek SJ. Gastric secretion and the pathogenesis of peptic ulcer in the Helicobacter pylori infection. J Physiol Pharmacol 1996;47:5–19.

  24. 8116_F000Iijima K, Shimosegawa T. Involvement of luminal nitric oxide in the pathogenesis of the gastroesophageal reflux disease spectrum: nitric oxide and esophagus. J Gastroenterol Hepatol 2014;29:898–905. doi: 10.1111/jgh.12548

  25. 8116_F000Fändriks L, von Bothmer C, Åne A. Intragastric nitric oxide/nitrite in Helicobacter pylori -infected subjects. Scand J Gastroenterol 2001;36:347–50. doi: 10.1080/00365520119610

  26. 8116_F000Lundberg JO, Weitzberg E, Lundberg JM, Alving K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 1994;35:1543–6. doi: 10.1136/gut.35.11.1543

  27. 8116_F000Shiotani A, Yanaoka K, Iguchi M, Saika A, Itoh H, Nishioka S. Helicobacter pylori infection reduces intraluminal nitric oxide in humans. J Gastroenterol 1999;34:668–74. doi: 10.1007/s005350050317

  28. 8116_F000Gobert AP, McGee DJ, Akhtar M, Mendz GL, Newton JC, Cheng Y, et al. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc Natl Acad Sci U S A 2001;98:13844–9. doi: 10.1073/pnas.241443798

  29. 8116_F000Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 2004;37:395–400. doi: 10.1016/j.freeradbiomed.2004.04.027

  30. 8116_F000Crabtree J. Gastric mucosal inflammatory responses to Helicobacter pylori. Aliment Pharmacol Ther 1996;10(Suppl. 1):29–37. doi: 10.1046/j.1365-2036.1996.22164003.x

  31. 8116_F000Seo JY, Yu J-H, Lim JW, Mukaida N, Kim H. Nitric oxide-induced IL-8 expression is mediated by NF-kappaB and AP-1 in gastric epithelial AGS cells. J Physiol Pharmacol Off J Pol Physiol Soc 2009;60(Sup7):101–6.

  32. 8116_F000Bochner BS, Schleimer RP. The role of adhesion molecules in human eosinophil and basophil recruitment. J Allergy Clin Immunol 1994;94:427–38. doi: 10.1016/0091-6749(94)90195-3

  33. 8116_F000Ellmark P, Ingvarsson J, Carlsson A, Lundin BS, Wingren C, Borrebaeck CAK. Identification of protein expression signatures associated with Helicobacter pylori infection and gastric adenocarcinoma using recombinant antibody microarrays. Mol Cell Proteomics 2006;5:1638–46. doi: 10.1074/mcp.M600170-MCP200

  34. 8116_F000Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, et al. Distinct mechanism of Helicobacter pylori-mediated NF-κB activation between gastric cancer cells and monocytic cells. J Biol Chem 2001;276:44856–64. doi: 10.1074/jbc.M105381200

  35. 8116_F000Crabtree JE, Wyatt JI, Trejdosiewicz LK, Peichl P, Nichols PH, Ramsay N, et al. Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J Clin Pathol 1994;47:61–6. doi: 10.1136/jcp.47.1.61

  36. 8116_F000Kim G, Kim J-E, Kang M-J, Jang A-R, Kim YR, Kim S, et al. Inhibitory effect of 1tetradecanol on Helicobacter pyloriinduced production of interleukin8 and vascular endothelial growth factor in gastric epithelial cells. Mol Med Rep 2017;16:9573–8. doi: 10.3892/mmr.2017.7793

  37. 8116_F000Dudar GK, D’Andrea LD, Di Stasi R, Pedone C, Wallace JL. A vascular endothelial growth factor mimetic accelerates gastric ulcer healing in an iNOS-dependent manner. Am J Physiol-Gastrointest Liver Physiol 2008;295:G374–81. doi: 10.1152/ajpgi.90325.2008

  38. 8116_F000Al-Saffar AKh, Meijer CH, Gannavarapu VR, Hall G, Li Y, Diaz Tartera HO, et al. Parallel changes in Harvey-Bradshaw Index, TNF α, and intestinal fatty acid binding protein in response to infliximab in Crohn’s disease. Gastroenterol Res Pract 2017;2017:1–8. doi: 10.1155/2017/1745918

  39. 8116_F000Shapiro KB, Hotchkiss JH. Induction of nitric oxide synthesis in murine macrophages by Helicobacter pylori. Cancer Lett 1996;102:49–56. doi: 10.1016/0304-3835(96)04154-7

  40. 8116_F000Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 2005;201:1257–68. doi: 10.1084/jem.20042028

Published
2021-10-11
How to Cite
Saaed, H. K., Chiggiato, L., Webb, D.-L., Rehnberg, A.-S., Rubio, C. A., Befrits, R., & Hellström, P. M. (2021). Elevated gaseous luminal nitric oxide and circulating IL-8 as features of <em>Helicobacter pylori</em&gt;-induced gastric inflammation. Upsala Journal of Medical Sciences, 126(1). https://doi.org/10.48101/ujms.v126.8116
Section
Original Articles