Journal of Gastroenterology

, Volume 40, Issue 10, pp 925–931 | Cite as

Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease

  • Akio Ido
  • Masatsugu Numata
  • Mayumi Kodama
  • Hirohito Tsubouchi
Review

Abstract

The repair of intestinal mucosal injuries is a tightly regulated process involving epithelial restitution, cell proliferation and maturation, and the dedifferentiation of epithelial cells. Deeper injuries also require additional repair mechanisms, including inflammatory processes, angiogenesis, and extracellular-matrix deposition. Once intestinal mucosal injury occurs, numerous growth factors and cytokines, including hepatocyte growth factor (HGF), keratinocyte growth factor, endothelial growth factor, epidermal growth factor, transforming growth factor-β1, intestinal trefoil factor, interleukin (IL)-1, and IL-2, are induced in both the intestinal lumen and submucosa, and these factors cooperatively stimulate epithelial mucosal repair. HGF, a major agent promoting hepatocyte proliferation, also modulates intestinal epithelial cell proliferation and migration, leading to the acceleration of intestinal mucosal repair. Additionally, the proteolytic activation of HGF, which is mediated by HGF activator, is essential for the regeneration of injured intestinal mucosa. Recently, several studies have shown that the administration of recombinant human HGF or HGF gene therapy abrogates disease severity in several animal models of inflammatory bowel disease (IBD). Recombinant human HGF will soon be available for administration to patients with fulminant hepatic failure. Although additional preclinical biological studies are required, HGF has the potential to be an important new treatment modality promoting intestinal mucosal repair in patients with IBD.

Key words

mucosal repair growth factor HGF HGF activator inflammatory bowel disease 

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References

  1. 1.
    Hanauer, SB, Present, DH 2003The state of the art in the management of inflammatory bowel diseaseRev Gastroenterol Disord2754045362Google Scholar
  2. 2.
    Sandborn, WJ, Hanauer, SB 1999Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safetyInflamm Bowel Dis511933PubMedGoogle Scholar
  3. 3.
    Murphy, MS 1998Growth factors and gastrointestinal tractNutrition147714CrossRefPubMedGoogle Scholar
  4. 4.
    Beck, PL, Podolsky, DK 1999Growth factors in inflammatory bowel diseaseInflamm Bowel Dis54460PubMedGoogle Scholar
  5. 5.
    Dignass, AU, Strum, A 2001Peptide growth factors in the intestineEur J Gastroenterol Hepatol1376370CrossRefPubMedGoogle Scholar
  6. 6.
    Dignass, AU 2001Mechanisms and modulation of intestinal epithelial repairInflamm Bowel Dis76877PubMedGoogle Scholar
  7. 7.
    Mammen, JMV, Matthews, JB 2003Mucosal repair in the gastrointestinal tractCrit Care Med31S5327CrossRefPubMedGoogle Scholar
  8. 8.
    Okamoto, R, Yajima, T, Yamazaki, M, Kanai, T, Mukai, M, Okamoto, S,  et al. 2002Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tractNat Med810117CrossRefPubMedGoogle Scholar
  9. 9.
    Okamoto, R, Watanabe, M 2004Molecular and clinical basis for the regeneration of human gastrointestinal epitheliaJ Gastroenterol3916CrossRefPubMedGoogle Scholar
  10. 10.
    Matsumoto, T, Okamoto, R, Yajima, T, Mori, T, Okamoto, S, Ikeda, Y,  et al. 2005Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestineGastroenterology128185167CrossRefPubMedGoogle Scholar
  11. 11.
    Gohda, E, Tsubouchi, H, Nakayama, H, Hirono, S, Takahashi, K, Koura, M,  et al. 1986Human hepatocyte growth factor in plasma of patients with fulminant hepatic failureExp Cell Res16613950CrossRefPubMedGoogle Scholar
  12. 12.
    Gohda, E, Tsubouchi, H, Nakayama, H, Hirono, S, Sakiyama, O, Takahashi, K,  et al. 1988Purification and partial characterization of hepatocyte growth factor of a patient with fulminant hepatic failureJ Clin Invest814149PubMedGoogle Scholar
  13. 13.
    Igawa, T, Kanda, S, Kanetake, H, Saitoh, Y, Ichihara, A, Tomita, Y,  et al. 1991Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cellsBiochem Biophys Res Commun1748318CrossRefPubMedGoogle Scholar
  14. 14.
    Joplin, R, Hishida, T, Tsubouchi, H, Daikuhara, Y, Ayres, R, Neuberger, JM,  et al. 1992Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factorJ Clin Invest9012849PubMedGoogle Scholar
  15. 15.
    Takahashi, M, Ota, S, Terano, A, Yoshiura, K, Matsumura, M, Miwa, Y,  et al. 1993Hepatocyte growth factor induces mitogenic reaction to the rabbit gastric epithelial cells in primary cultureBiochem Biophys Res Commun19152834CrossRefPubMedGoogle Scholar
  16. 16.
    Dignass, AU, Lynch-Devaney, K, Podolsky, DK 1994Hepatocyte growth factor/scatter factor modulates intestinal epithelial cell proliferation and migrationBiochem Biophys Res Commun2027019CrossRefPubMedGoogle Scholar
  17. 17.
    Lacy, ER 1988Epithelial restitution in the gastrointestinal tractJ Clin Gastroenterol10727Google Scholar
  18. 18.
    Feil, W, Wentzl, E, Vattay, P, Starlinger, M, Sogukoglu, T, Schiessel, R 1987Repair of rabbit duodenal mucosa after acid injury in vivo and in vitroGastroenterology92197386PubMedGoogle Scholar
  19. 19.
    Moore, R, Carlson, S, Madara, JL 1989Rapid barrier restitution in an in vitro model of intestinal epithelial injuryLab Invest6023744PubMedGoogle Scholar
  20. 20.
    McCormack, SA, Viar, MJ, Johnson, LR 1992Migration of IEC-6 cells: a model for mucosal healingAm J Physiol263G42635Google Scholar
  21. 21.
    Nusrat, A, Delp, C, Madara, J 1992Intestinal epithelial restitutionJ Clin Invest89150111PubMedGoogle Scholar
  22. 22.
    Part 1. Epithelial Restitution2002

    Gastrointestinal mucosal repair and experimental therapeutics

    Cho, CHWang, JY eds. Front Gastrointest Res, vol. 25KargerBasel
    Google Scholar
  23. 23.
    Grenier, A, Chollet-Martin, S, Crestani, B, Delarche, C, El Benna, J, Boutten, A,  et al. 2002Presence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophilsBlood9929973004CrossRefPubMedGoogle Scholar
  24. 24.
    Koehne, P, William, C, Strauss, E, Schindler, R, Eckardt, KU, Buhrer, C 2000Lack of hypoxic stimulation of VEGF secretion from neutrophils and plateletsAm J Physiol Heart Circ Physiol279H81724PubMedGoogle Scholar
  25. 25.
    Oka, Y, Orth, DN 1983Human plasma epidermal growth factor/S61538-urogastrone is associated with blood plateletsJ Clin Invest7224959PubMedGoogle Scholar
  26. 26.
    Assoian, RK, MB. Type, Sporn 1986S61538 transforming growth factor in human platelets: release during platelet degradation and action on vascular smooth muscle cellsJ Cell Biol102121723CrossRefPubMedGoogle Scholar
  27. 27.
    Karey, KP, Sirbasku, DA 1989Human platelet-derived mitogens: subcellular locarilation of insulin-like growth factor I to the S61537-granule and release in response to thrombinBlood741093100PubMedGoogle Scholar
  28. 28.
    Podolsky, DK 1999Innate mechanisms of mucosal defense and repair: the best offense is a good defenseAm J Physiol Gastrointest Liver Physiol277G4959Google Scholar
  29. 29.
    Matsuura, M, Okazaki, K, Nishio, A, Nakase, H, Tamaki, H, Uchida, K,  et al. 2005Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitisGastroenterology12897586CrossRefPubMedGoogle Scholar
  30. 30.
    Dignass, AU, Tsunekawa, S, Podolsky, DK 1994Fibroblast growth factors modulate intestinal epithelial cell growth and migrationGastroenterology106125462PubMedGoogle Scholar
  31. 31.
    Ciacci, C, Lind, SE, Podolsky, DK 1993Transforming growth factor beta regulation of migration in wounded rat intestinal epithelial monolayersGastroenterology10593101PubMedGoogle Scholar
  32. 32.
    Boros, P, Miller, CM 1995Hepatocyte growth factor: a multifunctional cytokineLancet3452935CrossRefPubMedGoogle Scholar
  33. 33.
    Zarnegar, R, Michalopoulos, GK 1995The many faces of hepatocyte growth factor: from hepatopoiesis to haemetopoiesisJ Cell Biol129117780CrossRefPubMedGoogle Scholar
  34. 34.
    Naka, D, Ishii, T, Yoshiyama, Y, Miyazawa, K, Hara, H, Hishida, T,  et al. 1992Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimerJ Biol Chem267201149PubMedGoogle Scholar
  35. 35.
    Shimomura, T, Ochiai, M, Kondo, J, Morimoto, Y 1992A novel protease obtained from FBS-containing culture supernatant that processes single-chain form hepatocyte growth factor to two-chain form in serum free cultureCytotechnology821929PubMedGoogle Scholar
  36. 36.
    Miyazawa, K, Shimomura, T, Kitamura, A, Kondo, J, Morimoto, Y, Kitamura, N 1993Molecular cloning and sequence analysis of the cDNA for a human serine protease responsible for activation of hepatocyte growth factorJ Biol Chem268100248PubMedGoogle Scholar
  37. 37.
    Itoh, H, Hamasuna, R, Kataoka, H, Yamauchi, M, Miyazawa, K, Kitamura, N,  et al. 2000Mouse hepatocyte growth factor activator gene: its expression not only in the liver but also in the gastrointestinal tractBiochim Biophys Acta1491295301PubMedGoogle Scholar
  38. 38.
    Shimomura, T, Kondo, J, Ochiai, M, Naka, D, Miyazawa, K, Morimoto, Y,  et al. 1993Activation of the zymogen of hepatocyte growth factor activator by thrombinJ Biol Chem2682292732PubMedGoogle Scholar
  39. 39.
    Miyazawa, K, Shimomura, T, Naka, D, Kitamura, N 1994Proteolytic activation of hepatocyte growth factor in response to tissue injuryJ Biol Chem269896670PubMedGoogle Scholar
  40. 40.
    Miyazawa, K, Shimomura, T, Kitamura, N 1996Activation of hepatocyte growth factor in the injured tissues is mediated by hepatocyte growth factor activatorJ Biol Chem27136158CrossRefPubMedGoogle Scholar
  41. 41.
    Hori, T, Ido, A, Uto, H, Hasuike, S, Moriuchi, A, Hayashi, K,  et al. 2004Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injuryJ Gastroenterol391339CrossRefPubMedGoogle Scholar
  42. 42.
    Shimomura, T, Denda, K, Kitamura, A, Kawaguchi, T, Kito, M, Kondo, J,  et al. 1997Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitorJ Biol Chem27263706CrossRefPubMedGoogle Scholar
  43. 43.
    Itoh, H, Kataoka, H, Tomita, M, Hamasuna, R, Nawa, Y, Kitamura, N,  et al. 2000Upregulation of HGF activator inhibitor type 1 but not type 2 along with regeneration of intestinal mucosaAm J Physiol Gastrointest Liver Physiol27863543Google Scholar
  44. 44.
    Kataoka, H, Shimomura, T, Kawaguchi, T, Hamasuna, R, Itoh, H, Kitamura, N,  et al. 2000Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironmentJ Biol Chem2754045362CrossRefPubMedGoogle Scholar
  45. 45.
    Takahashi, M, Ota, S, Simada, T, Hamada, E, Kawabe, T, Okudaira, T,  et al. 1995Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary cultureJ Clin Invest9519942003PubMedGoogle Scholar
  46. 46.
    Goke, M, Podolsky, DK 1996Regulation of the mucosal epithelial barrierBaillieres Clin Gastroenterol10393405CrossRefPubMedGoogle Scholar
  47. 47.
    Nishimura, S, Takahashi, M, Ota, S, Hirano, M, Hiraishi, H 1998Hepatocyte growth factor accelerates restitution of intestinal epithelial cellsJ Gastroenterol331728CrossRefPubMedGoogle Scholar
  48. 48.
    Nurstat, A, Parkos, CA, Bacarra, AE, Godowski, PJ, Delp-Archer, C, Rosen, EM,  et al. 1994Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epitheliumJ Clin Invest93205665PubMedGoogle Scholar
  49. 49.
    Kitamura, S, Kondo, S, Shimomura, Y, Isozaki, K, Kanayama, S, Higashimoto, Y,  et al. 2000Expression of hepatocyte growth factor and c-met in ulcerative colitisInflamm Res493204PubMedGoogle Scholar
  50. 50.
    Srivastava, M, Zurakowski, D, Cheifetz, P, Leichtner, A, Bousvaros, A 2001Elevated serum hepatocyte growth factor in children and young adults with inflammatory bowel diseaseJ Pediatr Gastroenterol Nutr3354853CrossRefPubMedGoogle Scholar
  51. 51.
    Matsuo, M, Shiota, G, Umeki, K, Kawasaki, H, Kojo, H, Miura, K 1997Induction of plasma hepatocyte growth factor in acute colitis of miceInflamm Res461667CrossRefPubMedGoogle Scholar
  52. 52.
    Ortega-Cava, CF, Ishihara, S, Kawashima, K, Rumi, MAK, Kazumori, H, Adachi, K,  et al. 2002Hepatocyte growth factor expression in dextran sodium sulfate-induced colitis in ratsDig Dis Sci47227585CrossRefPubMedGoogle Scholar
  53. 53.
    Xian, CJ, Couper, R, Howarth, GS, Read, LC, Kallincos, NC 2000Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositisBr J Cancer8294552CrossRefPubMedGoogle Scholar
  54. 54.
    Itoh, H, Naganuma, S, Takeda, N, Miyata, S, Uchinokura, S, Fukushima, T,  et al. 2004Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient miceGastroenterology127142335CrossRefPubMedGoogle Scholar
  55. 55.
    Okayasu, I, Hatakeyama, S, Yamada, M, Ohkusa, T, Inagaki, Y, Nakaya, R 1990A novel model in the induction of reliable experimental acute and chronic ulcerative colitis in miceGastroenterology98694702PubMedGoogle Scholar
  56. 56.
    Elson, CO, Sartor, RB, Tennyson, GS, Riddell, RH 1995Experimental models of inflammatory bowel diseaseGastroenterology109134467CrossRefPubMedGoogle Scholar
  57. 57.
    Tahara, Y, Ido, A, Yamamoto, S, Miyata, Y, Uto, H, Hori, T,  et al. 2003Hepatocyte growth factor facilitates colonic mucosal repair in experimental ulcerative colitis in ratsJ Pharmacol Exp Ther30714651CrossRefPubMedGoogle Scholar
  58. 58.
    Neurath, MF, Russ, I, Kelsall, BL, Stuber, E, Strober, W 1995Antibodies to interleukin 12 abrogate established experimental colitis in miceJ Exp Med182128190CrossRefPubMedGoogle Scholar
  59. 59.
    Hibi, T, Ogata, H, Sakuraba, A 2002Animal models of inflammatory bowel diseaseJ Gastroenterol3740917CrossRefPubMedGoogle Scholar
  60. 60.
    Numata, M, Ido, A, Moriuchi, A, Kim, ID, Tahara, Y, Yamamoto, S,  et al. 2005Hepatocyte growth factor facilitates the repair of large colonic ulcers in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in ratsInflamm Bowel Dis115518CrossRefPubMedGoogle Scholar
  61. 61.
    Kuroiwa, T, Kakishita, E, Hamano, T, Kataoka, Y, Seto, Y, Iwata, N,  et al. 2001Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic functionJ Clin Invest107136573PubMedGoogle Scholar
  62. 62.
    Oh, K, Iimuro, Y, Takeuchi, M, Kaneda, Y, Iwasaki, T, Terada, N,  et al. 2005Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine modelAm J Physiol Gastrointest Liver Physiol288G72935CrossRefPubMedGoogle Scholar
  63. 63.
    Hammer, RE, Makita, SD, Richardson, JA, Tang, JP, Taurog, JD 1990Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta2m: an animal model of HLA-B27-associated human disordersCell631099112CrossRefPubMedGoogle Scholar
  64. 64.
    Arthur, LG, Kuenzler, KA, Schwartz, MZ 2003Hepatocyte growth factor ameliorates inflammatory bowel disease in a rat modelJ Gastrointest Surg710628CrossRefPubMedGoogle Scholar
  65. 65.
    Arthur, LG, Schwartz, MZ, Kuenzler, KA, Birbe, R 2004Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel diseaseJ Pediatr Surg3913943CrossRefPubMedGoogle Scholar
  66. 66.
    Ohda, Y, Hori, K, Tomita, T, Hida, N, Kosaka, T, Fukuda, Y,  et al. 2005Effects of hepatocyte growth factor on rat inflammatory bowel disease modelsDig DIs Sci5091421CrossRefPubMedGoogle Scholar
  67. 67.
    Mukoyama, T, Kanbe, T, Murai, R, Murawaki, Y, Shimomura, T, Hashiguchi, K,  et al. 2005Therapeutic effect of adenoviral-mediated hepatocyte growth factor gene administration on TNBS-induced colitis in miceBiochem Biophys Res Commun329121724CrossRefPubMedGoogle Scholar
  68. 68.
    Sandborn, WJ, Sands, BE, Wolf, DC, Valentine, JF, Safdi, M, Katz, S,  et al. 2003Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trialAliment Pharmacol Ther17135564CrossRefPubMedGoogle Scholar
  69. 69.
    Sinha, A, Nightingale, JMD, West, KP, Berlanga-Acosta, J, Playford, RJ 2003Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitisNew Engl J Med3493507CrossRefPubMedGoogle Scholar
  70. 70.
    Ido, A, Moriuchi, A, Kim, ID, Numata, M, Nagata-Tsubouchi, Y, Hasuike, S,  et al. 2004Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal veinHepatol Res3017581CrossRefPubMedGoogle Scholar
  71. 71.
    Sakata, H, Takayama, H, Sharp, R, Rubin, JS, Merlino, G, LaRochelle, WJ 1996Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse liversCell Growth Differ7151323PubMedGoogle Scholar
  72. 72.
    Takayama, H, LaRochelle, WJ, Sharp, R, Otsuka, T, Kriebel, P, Anver, M,  et al. 1997Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factorProc Natl Acad Sci USA947016CrossRefPubMedGoogle Scholar
  73. 73.
    Gallego, MI, Bierie, B, Hennighausen, L 2003Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathwaysOncogene228498508CrossRefPubMedGoogle Scholar
  74. 74.
    Bell, A, Chen, Q, DeFrances, MC, Michalopoulos, GK, Zarnegar, R 1999The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic miceOncogene1888795CrossRefPubMedGoogle Scholar
  75. 75.
    Horiguchi, N, Takayama, H, Toyoda, M, Otsuka, T, Fukusato, T, Merlino, G,  et al. 2002Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamineOncogene2117919CrossRefPubMedGoogle Scholar
  76. 76.
    Nooman, FP, Otsuka, T, Bang, S, Anver, MR, Merlino, G 2000Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic miceCancer Res60373843PubMedGoogle Scholar
  77. 77.
    Takayama, H, LaRochelle, WJ, Anver, M, Bockman, DE, Merlino, G 1996Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest developmentProc Natl Acad Sci USA93586671CrossRefPubMedGoogle Scholar
  78. 78.
    Shiota, G, Kawasaki, H, Nakamura, T, Schmidt, EV 1995Characterization of double transgenic mice expressing hepatocyte growth factor and transforming growth factor S61537Res Commun Mol Pathol Pharmacol901724PubMedGoogle Scholar
  79. 79.
    Santoni-Rugiu, E, Preisegger, KH, Kiss, A, Audolfsson, T, Shiota, G, Schmidt, EV,  et al. 1996Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse modelProc Natl Acad Sci USA93957782CrossRefPubMedGoogle Scholar
  80. 80.
    Nakase, H, Okazaki, K, Tabata, Y, Ozeki, M, Watanabe, N, Ohana, M,  et al. 2002New cytokine delivery system using gelatin microspheres containing interleukin-10 for experimental inflammatory bowel diseaseJ Pharmacol Exp Ther3015965CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2005

Authors and Affiliations

  • Akio Ido
    • 1
  • Masatsugu Numata
    • 2
  • Mayumi Kodama
    • 2
  • Hirohito Tsubouchi
    • 1
    • 3
  1. 1.Department of Experimental Therapeutics, Translational Research CenterKyoto University HospitalKyotoJapan
  2. 2.Second department of Internal Medicine, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
  3. 3.Department of Digestive Disease and Life-style related DiseaseKagoshima University Graduate School of Medical and Dental ScienceKagoshimaJapan

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