Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

Clinical Science

Volumn 129, Issue 12, 2015, Pages 1107-1113

  Zorzi, Francesca ^a   Calabrese, Emma ^a   Monteleone, Giovanni ^a  

^a UNIVERSITY OF ROME TOR VERGATA   (Italy)

Author keywords

Collagen; Crohn's disease; Extracellular matrix; Smad; TGF 1

Indexed keywords

ATORVASTATIN; CAPTOPRIL; CASPASE; CILENGITIDE; COLLAGEN TYPE 1; ENALAPRILAT; LISINOPRIL; MESSENGER RNA; PROTEINASE; RESVERATROL; GASTROINTESTINAL AGENT;

AUTOPHAGY; CROHN DISEASE; EXTRACELLULAR MATRIX; FIBROGENESIS; GENETIC ANALYSIS; HUMAN; INTESTINAL FIBROSIS; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN TARGETING; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; ANIMAL; DISEASE MODEL; DRUG EFFECTS; FIBROSIS; GENETIC PREDISPOSITION; GENETIC VARIABILITY; GENETICS; INTESTINE; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; RISK FACTOR; SIGNAL TRANSDUCTION;

ANIMALS; CROHN DISEASE; DISEASE MODELS, ANIMAL; EXTRACELLULAR MATRIX; FIBROSIS; GASTROINTESTINAL AGENTS; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; HUMANS; INTESTINES; MOLECULAR TARGETED THERAPY; PHENOTYPE; RISK FACTORS; SIGNAL TRANSDUCTION;

EID: 84951927169     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20150472     Document Type: Review

References (91)

1. Cosnes, J., Cattan, S., Blain, A., Beaugerie, L., Carbonnel, F., Parc, R. and Gendre, J.P. (2002) Long-term evolution of disease behavior of Crohn's disease. Inflamm. Bowel Dis. 8, 244-250
2. Burke, J.P., Mulsow, J.J., O'Keane, C., Docherty, N.G., Watson, R.W. and O'Connell, P.R. (2007) Fibrogenesis in Crohn's disease. Am. J. Gastroenterol. 102, 439-448
3. Van Assche, G., Geboes, K. and Rutgeerts, P. (2004) Medical therapy for Crohn's disease strictures. Inflamm. Bowel Dis. 10, 55-60
4. Olaison, G., Smedh, K. and Sjodahl, R. (1992) Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut 33, 331-335
5. Rieder, F., Kessler, S., Sans, M. and Fiocchi, C. (2012) Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G786-G801
6. Wynn, T.A. and Ramalingam, T.R. (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028-1040
7. Ahmad, T., Armuzzi, A., Bunce, M., Mulcahy-Hawes, K., Marshall, S.E., Orchard, T.R., Crawshaw, J., Large, O., de Silva, A., Cook, J.T. et al. (2002) The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 122, 854-866
8. Cleynen, I., González, J.R., Figueroa, C., Franke, A., McGovern, D., Bortlík, M., Crusius, B.J., Vecchi, M., Artieda, M., Szczypiorska, M. et al. (2013) Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut 62, 1556-1565
9. Lesage, S., Zouali, H., Cézard, J.P., Colombel, J.F., Belaiche, J., Almer, S., Tysk, C., O'Morain, C., Gassull, M., Binder, V. et al. (2002) CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 70, 845-857
10. Abreu, M.T., Taylor, K.D., Lin, Y.C., Hang, T., Gaiennie, J., Landers, C.J., Vasiliauskas, E.A., Kam, L.Y., Rojany, M., Papadakis, K.A. et al. (2002) Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology 123, 679-688
11. Alvarez-Lobos, M., Arostegui, J.I., Sans, M., Tassies, D., Plaza, S., Delgado, S., Lacy, A.M., Pique, J.M., Yagüe, J. and Panés, J. (2005) Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence. Ann. Surg. 242, 693-700
12. Ogura, Y., Inohara, N., Benito, A., Chen, F.F., Yamaoka, S. and Nunez, G. (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812-4818
13. Shaw, M.H., Reimer, T., Kim, Y.G. and Nuñez, G. (2008) NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr. Opin. Immunol. 20, 377-382
14. Girardin, S.E., Viala, J., Chamaillard, M., Labigne, A., Thomas, G., Philpott, D.J. and Sansonetti, P.J. (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869-8872
15. Economou, M., Trikalinos, T.A., Loizou, K.T., Tsianos, E.V. and Ioannidis, J.P. (2004) Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am. J. Gastroenterol. 99, 2393-2404
16. Cuthbert, A.P., Fisher, S.A., Mirza, M.M., King, K., Hampe, J., Croucher, P.J., Mascheretti, S., Sanderson, J., Forbes, A., Mansfield, J. et al. (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122, 867-874
17. Ogura, Y., Inohara, N., Nicolae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.P. et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 599-603
18. Homer, C.R., Richmond, A.L., Rebert, N.A., Achkar, J.P. and McDonald, C. (2010) ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology 139, 1630-1641
19. Travassos, L.H., Carneiro, L.A., Ramjeet, M., Hussey, S., Kim, Y.G., Magalhães, J.G., Yuan, L., Soares, F., Chea, E., Le Bourhis, L. et al. (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55-62
20. Strisciuglio, C., Auricchio, R., Martinelli, M., Staiano, A., Giugliano, F.P., Andreozzi, M., De Rosa, M., Giannetti, E., Gianfrani, C., Izzo, P. et al. (2014) Autophagy genes variants and paediatric Crohn's disease phenotype: a single-centre experience. Dig. Liver Dis. 46, 512-517
21. Fowler, E.V., Doecke, J., Simms, L.A., Zhao, Z.Z., Webb, P.M., Hayward, N.K., Whiteman, D.C., Florin, T.H., Montgomery, G.W., Cavanaugh, J.A. et al. (2008) ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity. Am. J. Gastroenterol. 103, 2519-2526
22. Maeda, S., Hsu, L.C., Liu, H., Bankston, L.A., Iimura, M., Kagnoff, M.F., Eckmann, L. and Karin, M. (2005) Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 734-738
23. Sabate, J.M., Ameziane, N., Lamoril, J., Jouet, P., Farmachidi, J.P., Soulé, J.C., Harnois, F., Sobhani, I., Jian, R., Deybach, J.C. et al. (2008) The V249I polymorphism of the CX3CR1 gene is associated with fibrostenotic disease behavior in patients with Crohn's disease. Eur. J. Gastroenterol. Hepatol. 20, 748-755
24. Brand, S., Hofbauer, K., Dambacher, J., Schnitzler, F., Staudinger, T., Pfennig, S., Seiderer, J., Tillack, C., Konrad, A., Göke, B. et al. (2006) Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease phenotype. Am. J. Gastroenterol. 101, 99-106
25. Hume, G.E., Fowler, E.V., Lincoln, D., Eri, R., Templeton, D., Florin, T.H., Cavanaugh, J.A. and Radford-Smith, G.L. (2006) Angiotensinogen and transforming growth factor β1: novel genes in the pathogenesis of Crohn's disease. J. Med. Genet. 43, e51
26. Meijer, M.J., Mieremet-Ooms, M.A., van Hogezand, R.A., Lamers, C.B., Hommes, D.W. and Verspaget, H.W. (2007) Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-α single nucleotide gene polymorphisms in inflammatory bowel disease. World J. Gastroenterol. 13, 2960-2966
27. Lawrance, I.C., Rogler, G., Bamias, G., Breynaert, C., Florholmen, J., Pellino, G., Reif, S., Speca, S. and Latella, G. (2014) Cellular and molecular mediators of intestinal fibrosis. J. Crohns Colitis
28. Peyrin-Biroulet, L., Reinisch, W., Colombel, J.F., Mantzaris, G.J., Kornbluth, A., Diamond, R., Rutgeerts, P., Tang, L.K., Cornillie, F.J. and Sandborn, W.J. (2014) Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut 63, 88-95
29. Hanauer, S.B., Sandborn, W.J., Rutgeerts, P., Fedorak, R.N., Lukas, M., MacIntosh, D., Panaccione, R., Wolf, D. and Pollack, P. (2006) Human anti-tumor necrosis factor mono-clonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 130, 323-333
30. Rieder, F. and Fiocchi, C. (2008) Current knowledge and future perspectives. J. Crohns Colitis 2, 279-290
31. Fiocchi, C. and Lund, P.K. (2011) Themes in fibrosis and gastrointestinal inflammation. Am. J. Physiol. 300, G677-G683
32. Pucilowska, J.B., McNaughton, K.K., Mohapatra, N.K., Hoyt, E.C., Zimmermann, E.M., Sartor, R.B. and Lund, P.K. (2000) IGF-I and procollagen α1(I) are coexpressed in a subset of mesenchymal cells in active Crohn's disease. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1307-G1322
33. Stallmach, A., Schuppan, D., Riese, H.H., Matthes, H. and Riecken, E.O. (1992) Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn's disease. Gastroenterology 102, 1920-1929
34. Graham, M.F., Diegelmann, R.F., Elson, C.O., Lindblad, W.J., Gotschalk, N., Gay, S. and Gay, R. (1998) Collagen content and types in the intestinal strictures of Crohn's disease. Gastroenterology 94, 257-265
35. Becker, J.M. (1999) Surgical therapy for ulcerative colitis and Crohn's disease. Gastroenterol. Clin. North Am. 28, 371-390
36. Pucilowska, J.B., Williams, K.L. and Lund, P.K. (2000) Fibrogenesis. IV. Fibrosis and inflammatory bowel disease: cellular mediators and animal models. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G653-G659
37. Matthes, H., Herbst, H., Schuppan, D., Stallmach, A., Milani, S., Stein, H. and Riecken, E.O. (1992) Cellular localization of procollagen gene transcripts in inflammatory bowel diseases. Gastroenterology 102, 431-442
38. Louis, E., Ribbens, C., Godon, A., Franchimont, D., De Groote, D., Hardy, N., Boniver, J., Belaiche, J. and Malaise, M. (2000) Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. Clin. Exp. Immunol. 120, 241-246
39. Heuschkel, R.B., MacDonald, T.T., Monteleone, G., Bajaj-Elliott, M., Smith, J.A. and Pender, S.L. (2000) Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesion of children with inflammatory bowel disease. Gut 47, 57-62
40. Visse, R.N.H. (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827-839
41. Nagase, H. and Woessner, J.F. (1999) Matrix metalloproteinases. J. Biol. Chem. 274, 21491-21494
42. Gao, Q., Meijer, M.J., Kubben, F.J., Sier, C.F., Kruidenier, L., van Duijn, W., van den Berg, M., van Hogezand, R.A., Lamers, C.B. and Verspaget, H.W. (2005) Expression of matrix metalloproteinases-2 and 9 in intestinal tissue of patients with inflammatory bowel diseases. Dig. Liver Dis. 37, 584-592
43. Gomez, D.E., Alonso, D.F., Yoshiji, H. and Thorgeirsson, U.P. (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur. J. Cell Biol. 74, 111-122
44. Brew, K., Dinakarpandian, D. and Nagase, H. (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim. Biophys. Acta 1477, 267-283
45. McKaig, B.C., McWilliams, D., Watson, S.A. and Mahida, Y.R. (2003) Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease. Am. J. Pathol. 162, 1355-1360
46. Lawrance, I.C., Wu, F., Leite, A.Z., Willis, J., West, G.A., Fiocchi, C. and Chakravarti, S. (2003) A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-κB. Gastroenterology 125, 1750-1761
47. Rieder, F. and Fiocchi, C. (2009) Intestinal fibrosis in IBD: a dynamic, multifactorial process. Nat. Rev. Gastroenterol. Hepatol. 6, 228-235
48. Seki, E., De Minicis, S., Osterreicher, C.H., Kluwe, J., Osawa, Y., Brenner, D.A. and Schwabe, R.F. (2007) TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324-1333
49. Speca, S., Giusti, I., Rieder, F. and Latella, G. (2012) Cellular and molecular mechanisms of intestinal fibrosis. World J. Gastroenterol. 18, 3635-3661
50. Wynn, T.A. (2008) Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199-210
51. Otte, J.M., Rosenberg, I.M. and Podolsky, D.K. (2003) Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124, 1866-1878
52. Szebeni, B., Veres, G., Dezsofi, A., Vannay, A., Mraz, M., Majorova, E. and Arato, A. (2008) Increased expression of Toll-like receptor (TLR) 2 TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin. Exp. Immunol. 151, 34-41
53. Meneghin, A.H.C. (2007) Infectious disease, the immune response and fibrosis. J. Clin. Invest. 117, 530-538
54. Coelho, A.L., Hogaboam, C.M. and Kunkel, S.L. (2005) Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev. 16, 553-560
55. McKaig, B.C., Hughes, K., Tighe, P.J. and Mahida, Y.R. (2002) Differential expression of TGF-β isoforms by normal and inflammatory bowel disease intestinal myofibroblasts. Am. J. Physiol. Cell Physiol. 282, C172-C182
56. Leask, A. and Abraham, D.J. (2004) TGF-β signaling and the fibrotic response. FASEB J 18, 816-827
57. Di Sabatino, A., Jackson, C.L., Pickard, K.M., Buckley, M., Rovedatti, L., Leakey, N.A., Picariello, L., Cazzola, P., Monteleone, G., Tonelli, F. et al. (2009) Transforming growth factor β signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures. Gut 58, 777-789
58. Mulsow, J.J., Watson, R.W., Fitzpatrick, J.M. and O'Connell, P.R. (2005) Transforming growth factor-β promotes pro-fibrotic behavior by serosal fibroblasts via PKC and ERK1/2 mitogen activated protein kinase cell signaling. Ann. Surg. 242, 880-887
59. Lutz, M. and Knaus, P. (2002) Integration of the TGF-β pathway into the cellular signalling network. Cell. Signal. 14, 977-988
60. Monteleone, G., Pallone, F. and MacDonald, T.T. (2004) Smad7 in TGF-β-mediated negative regulation of gut inflammation. Trends Immunol 25, 513-517
61. de Caestecker, M.P., Parks, W.T., Frank, C.J., Castagnino, P., Bottaro, D.P., Roberts, A.B. and Lechleider, R.J. (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev. 12, 1587-1592
62. Brown, J.D., DiChiara, M.R., Anderson, K.R., Gimbrone, Jr, M.A. and Topper, J.N. (1999) MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J. Biol. Chem. 274, 8797-8805
63. Dennler, S., Prunier, C., Ferrand, N., Gauthier, J.M. and Atfi, A. (2000) c-Jun inhibits transforming growth factor β-mediated transcription by repressing Smad3 transcriptional activity. J. Biol. Chem. 275, 28858-28865
64. Leivonen, S.K., Häkkinen, L., Liu, D. and Kähäri, V.M. (2005) Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-β-induced expression of connective tissue growth factor in human fibroblasts. J. Invest. Dermatol. 124, 1162-1169
65. Hayashida, T., Decaestecker, M. and Schnaper, H.W. (2003) Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-β-dependent responses in human mesangial cells. FASEB J 17, 1576-1578
66. Monteleone, G., Neurath, M.F., Ardizzone, S., Di Sabatino, A., Fantini, M.C., Castiglione, F., Scribano, M.L., Armuzzi, A., Caprioli, F., Sturniolo, G.C. et al. (2015) Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N. Engl. J. Med. 372, 1104-1113
67. Monteleone, G., Fantini, M.C., Onali, S., Zorzi, F., Sancesario, G., Bernardini, S., Calabrese, E., Viti, F., Monteleone, I., Biancone, L. et al. (2012) Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. Mol. Ther. 20, 870-876
68. Zorzi, F., Calabrese, E., Monteleone, I., Fantini, M., Onali, S., Biancone, L., Pallone, F. and Monteleone, G. (2012) A phase 1 open-label trial shows that Smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn's disease. Aliment. Pharmacol. Ther. 36, 850-857
69. Jobson, T.M., Billington, C.K. and Hall, I.P. (1998) Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation. J. Clin. Invest. 101, 2650-2657
70. Kuemmerle, J.F. (1997) Autocrine regulation of growth in cultured human intestinal muscle by growth factors. Gastroenterology 113, 817-824
71. Simmons, J.G., Pucilowska, J.B., Keku, T.O. and Lund, PK. (2002) IGF-I and TGF-β1 have distinct effects on phenotype and proliferation of intestinal fibroblasts. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G809-G818
72. Kuemmerle, J.F. (2005) Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 β activity. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G101-G110
73. Kuemmerle, J.F. (2003) IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G411-G422
74. Kuemmerle, J.F. and Bushman, T.L. (1998) IGF-I stimulates intestinal muscle cell growth by activating distinct PI 3-kinase and MAP kinase pathways. Am. J. Physiol. 275, G151-G158
75. Flynn, R.S., Murthy, K.S., Grider, J.R., Kellum, J.M. and Kuemmerle, J.F. (2010) Endogenous IGF-I and aVβ3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn's disease. Gastroenterology 138, 285-293
76. Li, C. and Kuemmerle, J.F. (2014) Mechanisms that mediate the development of fibrosis in patients with Crohn's disease. Inflamm. Bowel Dis. 20, 1250-1258
77. Garcia, P., Schmiedlin-Ren, P., Mathias, J.S., Tang, H., Christman, G.M. and Zimmermann, E.M. (2012) Resveratrol causes cell cycle arrest, decreased collagen synthesis, and apoptosis in rat intestinal smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G326-G335
78. Li, P., Liang, M.L., Zhu, Y., Gong, Y.Y., Wang, Y., Heng, D. and Lin, L. (2014) Resveratrol inhibits collagen I synthesis by suppressing IGF-1R activation in intestinal fibroblasts. World J. Gastroenterol. 20, 4648-4661
79. Rahal, K., Schmiedlin-Ren, P., Adler, J., Dhanani, M., Sultani, V., Rittershaus, A.C., Reingold, L., Zhu, J., McKenna, B.J., Christman, G.M. et al. (2012) Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan-polysaccharide rat model of Crohn's disease. Inflamm. Bowel Dis. 18, 613-623
80. Li, J., Qu, X., Ricardo, S.D., Bertram, J.F. and Nikolic-Paterson, D.J. (2010) Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3. Am. J. Pathol. 177, 1065-1071
81. Caruso, R., Marafini, I., Franzè, E., Stolfi, C., Zorzi, F., Monteleone, I., Caprioli, F., Colantoni, A., Sarra, M., Sedda, S. et al. (2014) Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut. Mucosal Immunol 7, 1467-1479
82. Li, C., Flynn, R.S., Grider, J.R., Murthy, K.S., Kellum, J.M., Akbari, H. and Kummerle, J.F. (2013) Increased activation of latent TGFβ1 by aVβ3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide. Inflamm. Bowel Dis. 144, 259-268
83. Paul, M., Poyan Mehr, A. and Kreutz, R. (2006) Physiology of local renin-angiotensin systems. Physiol. Rev. 86, 747-803
84. Spencer, A.U., Yang, H., Haxhija, E.Q., Wildhaber, B.E., Greenson, J.K. and Teitelbaum, D.H. (2007) Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition. Dig. Dis. Sci. 52, 1060-1070
85. Wildhaber, B.E., Yang, H., Haxhija, E.Q., Spencer, A.U. and Teitelbaum, D.H. (2005) Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 10, 1305-1315
86. Hirasawa, K., Sato, Y., Hosoda, Y., Yamamoto, T. and Hanai, H. (2002) Immunohistochemical localization of angiotensin II receptor and local renin-angiotensin system in human colonic mucosa. J. Histochem. Cytochem. 50, 275-282
87. Koga, H., Yang, H., Adler, J., Zimmermann, E.M. and Teitelbaum, D.H. (2008) Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse model: development of a unique mode of treatment. Surgery 144, 259-268
88. Wengrower, D., Zanninelli, G., Pappo, O., Latella, G., Sestieri, M., Villanova, A., Faitelson, Y., Pines, M. and Goldin, E. (2004) Prevention of fibrosis in experimental colitis by captopril: the role of TGF-β1. Inflamm. Bowel Dis. 10, 536-545
89. Jahovic, N., Ercan, F., Gedik, N., Yüksel, M., Sener, G. and Alican, I. (2005) The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats. Regul. Pept. 130, 67-74
90. Grip, O. and Janciauskiene, S. (2009) Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn's disease. PLoS One 4, e5263
91. Grip, O., Janciauskiene, S. and Bredberg, A. (2008) Use of atorvastatin as an anti-inflammatory treatment in Crohn's disease. Br. J. Pharmacol. 155, 1085-1092