1887

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Volume 60, Issue 8

Role of the haem oxygenase/carbon monoxide pathway in toxin A-induced enteritis in mice Free

Abstract

is the major cause of antibiotic-associated colitis, a disease with significant morbidity and mortality. This study investigated the role of the haem oxygenase-1 (HO-1)/carbon monoxide (CO) pathway in toxin A-induced enteritis in mice. The HO substrate haemin, zinc protoporphyrin IX (ZnPP IX), a specific HO-1 inhibitor, dimanganese decacarbonyl (DMDC), a CO donor, or an equivalent volume of their respective vehicles were injected subcutaneously 30 min prior to local challenge with toxin A (25 or 50 µg per ileal loop) or PBS. Intestinal ileal loop weight/length ratios were calculated 3 h later. Ileal tissues were collected for histological analysis and measurement of myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) production by ELISA and immunohistochemistry for HO-1. Treatment of mice subjected to toxin A (TcdA) with haemin or DMDC prevented oedema, mucosal disruption and neutrophil infiltration observed in histological analysis. It also decreased TcdA-induced MPO activity and TNF-α or IL-1β production. In contrast, the specific HO-1 inhibitor (ZnPP IX) exacerbated all these evaluated parameters. TcdA increased HO-1 expression as seen by immunohistochemistry. These results suggest that the HO-1/CO pathway exerts a protective role in TcdA-induced enteritis and that its pharmacological modulation might be important for the management of associated disease.

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© 2011 SGM
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2011-08-01
2024-04-18
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References

  1. Abraham N. G., Lin J. H., Schwartzman M. L., Levere R. D., Shibahara S. 1988; The physiological significance of heme oxygenase. Int J Biochem 20:543–558 [View Article][PubMed]
     [Google Scholar]
  2. Bradley P. P., Christensen R. D., Rothstein G. 1982; Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 60:618–622[PubMed]
     [Google Scholar]
  3. Brito G. A., Fujji J., Carneiro-Filho B. A., Lima A. A., Obrig T., Guerrant R. L. 2002a; Mechanism of Clostridium difficile toxin A-induced apoptosis in T84 cells. J Infect Dis 186:1438–1447 [View Article][PubMed]
     [Google Scholar]
  4. Brito G. A., Sullivan G. W., Ciesla W. P. Jr, Carper H. T., Mandell G. L., Guerrant R. L. 2002b ). Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function. J Infect Dis 185:1297–1306 [View Article][PubMed]
     [Google Scholar]
  5. Castagliuolo I., Riegler M., Pasha A., Nikulasson S., Lu B., Gerard C., Gerard N. P., Pothoulakis C. 1998; Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J Clin Invest 101:1547–1550 [View Article][PubMed]
     [Google Scholar]
  6. Cavalcante I. C., Castro M. V., Barreto A. R., Sullivan G. W., Vale M., Almeida P. R., Linden J., Rieger J. M., Cunha F. Q. et al. 2006; Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis. Infect Immun 74:2606–2612 [View Article][PubMed]
     [Google Scholar]
  7. Dal Secco D., Paron J. A., de Oliveira S. H., Ferreira S. H., Silva J. S., Cunha F. de Q. 2003; Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis. Nitric Oxide 9:153–164 [View Article][PubMed]
     [Google Scholar]
  8. Dearden D. V., Hayashibara K., Beauchamp J. L., Kirchner N. J., van Koppen P. A. M., Bowers M. T. 1989; Fundamental studies of the energetics and dynamics of ligand dissociation and exchange processes at transition-metal centers in the gas phase: Mn(CO)x+, x = 1–6. J Am Chem Soc 111:2401–2409 [View Article]
     [Google Scholar]
  9. Flegel W. A., Müller F., Däubener W., Fischer H. G., Hadding U., Northoff H. 1991; Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun 59:3659–3666[PubMed]
     [Google Scholar]
  10. Freitas A., Alves-Filho J. C., Secco D. D., Neto A. F., Ferreira S. H., Barja-Fidalgo C., Cunha F. Q. 2006; Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation. Br J Pharmacol 149:345–354 [View Article][PubMed]
     [Google Scholar]
  11. Gomes A. S., Gadelha G. G., Lima S. J., Garcia J. A., Medeiros J. V., Havt A., Lima A. A., Ribeiro R. A., Brito G. A. et al. 2010; Gastroprotective effect of heme-oxygenase 1/biliverdin/CO pathway in ethanol-induced gastric damage in mice. Eur J Pharmacol 642:140–145 [CrossRef]
     [Google Scholar]
  12. Hayashi S., Takamiya R., Yamaguchi T., Matsumoto K., Tojo S. J., Tamatani T., Kitajima M., Makino N., Ishimura Y., Suematsu M. 1999; Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res 85:663–671[PubMed] [CrossRef]
     [Google Scholar]
  13. Hegazi R. A., Rao K. N., Mayle A., Sepulveda A. R., Otterbein L. E., Plevy S. E. 2005; Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 202:1703–1713 [View Article][PubMed]
     [Google Scholar]
  14. Inui M., Ishida Y., Kimura A., Kuninaka Y., Mukaida N., Kondo T. 2011; Protective roles of CX3CR1-mediated signals in toxin A-induced enteritis through the induction of heme oxygenase-1 expression. J Immunol 186:423–431[PubMed] [CrossRef]
     [Google Scholar]
  15. Johnson T. R., Mann B. E., Clark J. E., Foresti R., Green C. J., Motterlini R. 2003; Metal carbonyls: a new class of pharmaceuticals?. Angew Chem Int Ed Engl 42:3722–3729 [View Article][PubMed]
     [Google Scholar]
  16. Jun C. D., Kim Y., Choi E. Y., Kim M., Park B., Youn B., Yu K., Choi K. S., Yoon K. H. et al. 2006; Gliotoxin reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice: evidence of the connection between heme oxygenase-1 and the nuclear factor-kappaB pathway in vitro and in vivo. Inflamm Bowel Dis 12:619–629 [View Article][PubMed]
     [Google Scholar]
  17. Kelly C. P., LaMont J. T. 1998; Clostridium difficile infection. Annu Rev Med 49:375–390 [View Article][PubMed]
     [Google Scholar]
  18. Kelly C. P., Becker S., Linevsky J. K., Joshi M. A., O’Keane J. C., Dickey B. F., LaMont J. T., Pothoulakis C. 1994a; Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest 93:1257–1265 [View Article][PubMed]
     [Google Scholar]
  19. Kelly C. P., Becker S., Linevsky J. K., Joshi M. A., O’Keane J. C., Dickey B. F., LaMont J. T., Pothoulakis C. 1994b ). Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest 93:1257–1265 [View Article][PubMed]
     [Google Scholar]
  20. Kirkwood K. S., Bunnett N. W., Maa J., Castagliolo I., Liu B., Gerard N., Zacks J., Pothoulakis C., Grady E. F. 2001; Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile toxin A. Am J Physiol Gastrointest Liver Physiol 281:G544–G551[PubMed]
     [Google Scholar]
  21. Kuehne S. A., Cartman S. T., Heap J. T., Kelly M. L., Cockayne A., Minton N. P. 2010; The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711–713 [View Article][PubMed]
     [Google Scholar]
  22. Lyras D., O’Connor J. R., Howarth P. M., Sambol S. P., Carter G. P., Phumoonna T., Poon R., Adams V., Vedantam G. et al. 2009; Toxin B is essential for virulence of Clostridium difficile . Nature 458:1176–1179 [View Article][PubMed]
     [Google Scholar]
  23. Maines M. D., Trakshel G. M., Kutty R. K. 1986; Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 261:411–419[PubMed]
     [Google Scholar]
  24. McCoubrey W. K. Jr, Huang T. J., Maines M. D. 1997; Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247:725–732 [View Article][PubMed]
     [Google Scholar]
  25. Morse D., Pischke S. E., Zhou Z., Davis R. J., Flavell R. A., Loop T., Otterbein S. L., Otterbein L. E., Choi A. M. 2003; Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem 278:36993–36998 [View Article][PubMed]
     [Google Scholar]
  26. Otterbein L. E., Choi A. M. 2000; Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279:L1029–L1037[PubMed]
     [Google Scholar]
  27. Otterbein L. E., Bach F. H., Alam J., Soares M., Tao Lu H., Wysk M., Davis R. J., Flavell R. A., Choi A. M. 2000; Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428 [View Article][PubMed]
     [Google Scholar]
  28. Paine A., Eiz-Vesper B., Blasczyk R., Immenschuh S. 2010; Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 80:1895–1903 [View Article][PubMed]
     [Google Scholar]
  29. Paul G., Bataille F., Obermeier F., Bock J., Klebl F., Strauch U., Lochbaum D., Rümmele P., Farkas S. et al. 2005; Analysis of intestinal haem-oxygenase-1 (HO-1) in clinical and experimental colitis. Clin Exp Immunol 140:547–555 [View Article][PubMed]
     [Google Scholar]
  30. Pothoulakis C., LaMont J. T. 2001; Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am J Physiol Gastrointest Liver Physiol 280:G178–G183[PubMed]
     [Google Scholar]
  31. Pothoulakis C., Barone L. M., Ely R., Faris B., Clark M. E., Franzblau C., LaMont J. T. 1986; Purification and properties of Clostridium difficile cytotoxin B. J Biol Chem 261:1316–1321[PubMed]
     [Google Scholar]
  32. Pothoulakis C., Castagliuolo I., LaMont J. T. 1998; Nerves and intestinal mast cells modulate responses to enterotoxins. News Physiol Sci 13:58–63[PubMed]
     [Google Scholar]
  33. Safieh-Garabedian B., Poole S., Allchorne A., Winter J., Woolf C. J. 1995; Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol 115:1265–1275[PubMed] [CrossRef]
     [Google Scholar]
  34. Siow R. C., Sato H., Mann G. E. 1999; Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?. Cardiovasc Res 41:385–394 [View Article][PubMed]
     [Google Scholar]
  35. Soares M. P., Seldon M. P., Gregoire I. P., Vassilevskaia T., Berberat P. O., Yu J., Tsui T. Y., Bach F. H. 2004; Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol 172:3553–3563[PubMed] [CrossRef]
     [Google Scholar]
  36. Suematsu M., Wakabayashi Y., Ishimura Y. 1996; Gaseous monoxides: a new class of microvascular regulator in the liver. Cardiovasc Res 32:679–686[PubMed] [CrossRef]
     [Google Scholar]
  37. Vachharajani T. J., Work J., Issekutz A. C., Granger D. N. 2000; Heme oxygenase modulates selectin expression in different regional vascular beds. Am J Physiol Heart Circ Physiol 278:H1613–H1617[PubMed]
     [Google Scholar]
  38. Varga C., Laszlo F., Fritz P., Cavicchi M., Lamarque D., Horvath K., Posa A., Berko A., Whittle B. J. 2007; Modulation by heme and zinc protoporphyrin of colonic heme oxygenase-1 and experimental inflammatory bowel disease in the rat. Eur J Pharmacol 561:164–171 [View Article][PubMed]
     [Google Scholar]
  39. Vicente A. M., Guillén M. I., Habib A., Alcaraz M. J. 2003; Beneficial effects of heme oxygenase-1 up-regulation in the development of experimental inflammation induced by zymosan. J Pharmacol Exp Ther 307:1030–1037 [View Article][PubMed]
     [Google Scholar]
  40. Vijayan V., Mueller S., Baumgart-Vogt E., Immenschuh S. 2010; Heme oxygenase-1 as a therapeutic target in inflammatory disorders of the gastrointestinal tract. World J Gastroenterol 16:3112–3119 [View Article][PubMed]
     [Google Scholar]
  41. Wagener F. A., van Beurden H. E., von den Hoff J. W., Adema G. J., Figdor C. G. 2003; The heme-heme oxygenase system: a molecular switch in wound healing. Blood 102:521–528 [View Article][PubMed]
     [Google Scholar]
  42. Wang W. P., Guo X., Koo M. W., Wong B. C., Lam S. K., Ye Y. N., Cho C. H. 2001; Protective role of heme oxygenase-1 on trinitrobenzene sulfonic acid-induced colitis in rats. Am J Physiol Gastrointest Liver Physiol 281:G586–G594[PubMed]
     [Google Scholar]
  43. Willis D., Moore A. R., Frederick R., Willoughby D. A. 1996; Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2:87–90 [View Article][PubMed]
     [Google Scholar]
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Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice
J. Med. Microbiol. 60, 1146 (2011); https://doi.org/10.1099/jmm.0.028910-0
/content/journal/jmm/10.1099/jmm.0.028910-0
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