Journal of Gastroenterology

, Volume 41, Issue 4, pp 318–324 | Cite as

Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

  • Yuichi Morohoshi
  • Katsuyoshi Matsuoka
  • Hiroshi Chinen
  • Nobuhiko Kamada
  • Toshiro Sato
  • Tadakazu Hisamatsu
  • Susumu Okamoto
  • Nagamu Inoue
  • Hiromasa Takaishi
  • Haruhiko Ogata
  • Yasushi Iwao
  • Toshifumi Hibi
Article

Abstract

Background

Neutrophil elastase (NE) is a major secretory product from activated neutrophils and a major contributor to tissue destruction. However, little is known about the pathogenic contribution of NE to ulcerative colitis (UC). This study was designed to investigate the contribution of NE by measuring NE activity in plasma and colonic mucosal tissue from UC patients and a murine acute colitis model, and to elucidate the therapeutic effect of the NE-specific inhibitor ONO-5046.

Methods

The NE enzyme activities in plasma and colonic mucosal tissue from UC patients were directly measured using an enzyme–substrate reaction. Acute colitis was induced in mice by administration of 1.5% dextran sulfate sodium (DSS) for 5 days. DSS-induced colitis mice were then treated with ONO-5046 (50 mg/kg body weight) intraperitoneally twice a day.

Results

In UC patients, the NE enzyme activity was significantly elevated in both the plasma and colonic mucosal tissue compared with healthy controls. In DSS-induced colitis mice, the NE enzyme activity increased in parallel with the disease development. ONO-5046 showed therapeutic effects in DSS-treated mice by significantly reducing weight loss and histological score. ONO-5046 suppressed the NE enzyme activities in both plasma and culture supernatant of colonic mucosa from DSS-induced colitis mice.

Conclusions

ONO-5046, a specific NE inhibitor, prevented the development of DSS-induced colitis in mice. NE therefore represents a promising target for the treatment of UC patients.

Key words

ulcerative colitis neutrophil elastase dextran sulfate sodium-induced colitis ONO-5046 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Podolsky, DK 2002Inflammatory bowel diseaseN Engl J Med34741759PubMedCrossRefGoogle Scholar
  2. 2.
    Fiocchi, C 1998Inflammatory bowel disease: etiology and pathogenesisGastroenterology115182205PubMedCrossRefGoogle Scholar
  3. 3.
    Raab, Y, Gerdin, B, Ahlstedt, S, Hallgren, R 1993Neutrophil mucosal involvement is accompanied by enhanced local production of interleukin-8 in ulcerative colitisGut3412036PubMedGoogle Scholar
  4. 4.
    Balazs, M, Kovacs, A 1989Ulcerative colitis: electron microscopic studies with special reference to development of crypt abscessesDis Colon Rectum3232734PubMedGoogle Scholar
  5. 5.
    Shimoyama, T, Sawada, K, Hiwatashi, N, Sawada, T, Matsueda, K, Munadata, A,  et al. 2001Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter studyJ Clin Apheresis1619PubMedCrossRefGoogle Scholar
  6. 6.
    Bolognesi, M, Djinovic-Carugo, K, Ascenzi, P 1994Molecular bases for human leucocyte elastase inhibitionMonaldi Arch Chest Dis491449PubMedGoogle Scholar
  7. 7.
    Dallegri, F, Ottonello, L 1997Tissue injury in neutrophilic inflammationInflamm Res4638291PubMedCrossRefGoogle Scholar
  8. 8.
    Weiss, SJ 1989Tissue destruction by neutrophilsN Engl J Med32036576PubMedCrossRefGoogle Scholar
  9. 9.
    Gouni-Berthold, I, Baumeister, B, Wegel, E, Berthold, HK, Vetter, H, Schmidt, C 1999Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity?Hepatogastroenterology46231520PubMedGoogle Scholar
  10. 10.
    Kuno, Y, Ina, K, Nishiwaki, T, Tsuzuki, T, Shimada, M, Imada, A,  et al. 2002Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitisJ Gastroenterol37 Suppl 142232PubMedGoogle Scholar
  11. 11.
    Saitoh, O, Sugi, K, Matsuse, R, Uchida, K, Matsumoto, H, Nakagawa, K,  et al. 1995The forms and the levels of fecal PMN-elastase in patients with colorectal diseasesAm J Gastroenterol9038893PubMedGoogle Scholar
  12. 12.
    Adeyemi, EO, Neumann, S, Chadwick, VS, Hodgson, HJ, Pepys, MB 1985Circulating human leucocyte elastase in patients with inflammatory bowel diseaseGut26130611PubMedGoogle Scholar
  13. 13.
    Hagio, T, Nakao, S, Matsuoka, H, Matsumoto, S, Kawabata, K, Ohno, H 2001Inhibition of neutrophil elastase activity attenuates complement-mediated lung injury in the hamsterEur J Pharmacol4261318PubMedCrossRefGoogle Scholar
  14. 14.
    Yoshida, N, Sugimoto, N, Ochiai, J, Nakamura, Y, Ichikawa, H, Naito, Y,  et al. 2002Role of elastase and active oxygen species in gastric mucosal injury induced by aspirin administration in Helicobacter pylori-infected Mongolian gerbilsAliment Pharmacol Ther16 Supple 21917CrossRefGoogle Scholar
  15. 15.
    Tonai, T, Shiba, K, Taketani, Y, Ohmoto, Y, Murata, K, Muraguchi, M,  et al. 2001A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in ratsJ Neurochem78106472PubMedCrossRefGoogle Scholar
  16. 16.
    Kakimoto, K, Matsukawa, A, Yoshinaga, M, Nakamura, H 1995Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritisCell Immunol1652632PubMedCrossRefGoogle Scholar
  17. 17.
    Gower-Rousseau, C, Salomez, JL, Dupas, JL, Marti, R, Nuttens, MC, Votte, A,  et al. 1994Incidence of inflammatory bowel disease in northern France (1988–1990)Gut3514338PubMedGoogle Scholar
  18. 18.
    Lennard-Jones, JE 1989Classification of inflammatory bowel diseaseScand J Gastroenterol Suppl17026discussion 16–19PubMedGoogle Scholar
  19. 19.
    Lichtiger, S, Present, DH, Kornbluth, A, Gelernt, I, Bauer, J, Galler, G,  et al. 1994Cyclosporine in severe ulcerative colitis refractory to steroid therapyN Engl J Med33018415PubMedCrossRefGoogle Scholar
  20. 20.
    Siegmund, B, Fantuzzi, G, Rieder, F, Gamboni-Robertson, F, Lehr, HA, Hartmann, G,  et al. 2001Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha productionAm J Physiol Regul Integr Comp Physiol281R126473PubMedGoogle Scholar
  21. 21.
    Siegmund, B, Rieder, F, Albrich, S, Wolf, K, Bidlingmaier, C, Firestein, GS,  et al. 2001Adenosine kinase inhibitor GP515 improves experimental colitis in miceJ Pharmacol Exp Ther29699105PubMedGoogle Scholar
  22. 22.
    Nakajima, K, Powers, JC, Ashe, BM, Zimmerman, M 1979Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates related to the alpha 1-protease inhibitor reactive siteJ Biol Chem254402732PubMedGoogle Scholar
  23. 23.
    Young, RE, Thompson, RD, Larbi, KY, La, M, Roberts, CE, Shapiro, SD,  et al. 2004Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivoJ Immunol1724493502PubMedGoogle Scholar
  24. 24.
    Ishihara, K, Yamaguchi, Y, Okabe, K, Ogawa, M 1999Neutrophil elastase enhances macrophage production of chemokines in receptor-mediated reactionRes Commun Mol Pathol Pharmacol10313947PubMedGoogle Scholar
  25. 25.
    Vandivier, RW, Fadok, VA, Hoffmann, PR, Bratton, DL, Penvari, C, Brown, KK,  et al. 2002Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasisJ Clin Invest10966170PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2006

Authors and Affiliations

  • Yuichi Morohoshi
    • 1
  • Katsuyoshi Matsuoka
    • 1
  • Hiroshi Chinen
    • 1
  • Nobuhiko Kamada
    • 1
  • Toshiro Sato
    • 1
  • Tadakazu Hisamatsu
    • 1
  • Susumu Okamoto
    • 1
  • Nagamu Inoue
    • 2
  • Hiromasa Takaishi
    • 2
  • Haruhiko Ogata
    • 3
  • Yasushi Iwao
    • 2
  • Toshifumi Hibi
    • 1
    • 2
  1. 1.Department of Internal Medicine, School of MedicineKeio UniversityTokyoJapan
  2. 2.Center for Comprehensive and Advanced MedicineKeio UniversityTokyoJapan
  3. 3.Center for Diagnostic and Therapeutic EndoscopyKeio UniversityTokyoJapan

Personalised recommendations