Immunologie der Stenoseentstehung bei Morbus Crohn

Zusammenfassung

Mehr als ein Drittel der Patienten mit Morbus Crohn entwickeln intestinale Stenosen mit nachfolgender Notwendigkeit einer chirurgischen Therapie. Während die Pathophysiologie der Entzündungsreaktion des Morbus Crohn intensiv untersucht wird, ist das Wissen über die Fibrogenese eher mangelhaft. Der fibrotische intestinale Organumbau resultiert aus einem komplexen Zusammenspiel von genetischen Faktoren, akuten und chronischen Entzündungsreaktionen, Aktivierung von mesenchymalen Zellen und der zeitgerechten Expression von verschiedenen proinflammatorischen und profibrotischen Zytokinen. Die Kombination dieser Faktoren bedingt die überschießende Ablagerung extrazellulärer Matrix mit konsekutiver Fibrose des Intestinums. Durch die Erforschung der pathophysiologischen Grundlagen der Fibrogenese des Morbus Crohn kann die Basis für eine spezifische antifibrotische Therapie gebildet werden.

Abstract

Over one-third of patients with Crohn's disease eventually will develop intestinal stenosis with the need for surgical intervention. While the pathophysiology of the inflammatory response in Crohn's disease has been investigated extensively, the knowledge of intestinal fibrogenesis is limited. Fibrotic organ remodelling results from a complex interplay of genetic factors, acute and chronic inflammation, activation of mesenchymal cells and the timely expression of several proinflammatory and profibrotic cytokines. The combination of those factors leads to enhanced deposition of extracellular matrix with consecutive fibrosis of the intestine. Through investigation of the pathophysiologic processes of the fibrogenesis in Crohn's disease the basis for specific antifibrotic therapies can be built.

Fibrose - Stenose - Morbus Crohn

Fibrosis - Stenosis - Crohn's disease

Literatur

• 1 Van Assche G, Geboes K, Rutgeerts P. Medical therapy for Crohn's disease strictures.  Inflammatory Bowel Diseases. 2004;  10 55-60
• 2 Lichtenstein G R, Olson A, Travers S. et al . Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease.  The American Journal of Gastroenterology. 2006;  101 1030-1038
• 3 Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease.  The Journal of Clinical Investigation. 2007;  117 514-521
• 4 Hugot J P, Chamaillard M, Zouali H. et al . Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.  Nature. 2001;  411 599-603
• 5 Ogura Y, Bonen D K, Inohara N. et al . A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.  Nature. 2001;  411 603-606
• 6 Lesage S, Zouali H, Cezard J P. et al . CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.  American Journal of Human Genetics. 2002;  70 845-857
• 7 Hugot J P. Genetic origin of IBD.  Inflammatory Bowel Diseases. 2004;  10 Suppl 1 11-15
• 8 Hugot J P, Laurent-Puig P, Gower-Rousseau C. et al . Mapping of a susceptibility locus for Crohn's disease on chromosome 16.  Nature. 1996;  379 821-823
• 9 Maeda S, Hsu L C, Liu H. et al . Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing.  Science (New York, NY). 2005;  307 734-738
• 10 Abreu M T, Taylor K D, Lin Y C. et al . Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease.  Gastroenterology. 2002;  123 679-688
• 11 Ahmad T, Armuzzi A, Bunce M. et al . The molecular classification of the clinical manifestations of Crohn's disease.  Gastroenterology. 2002;  122 854-866
• 12 Sans M, Tassies D, Pellise M. et al . The 4G/4G genotype of the 4G/5G polymorphism of the type-1 plasminogen activator inhibitor (PAI-1) gene is a determinant of penetrating behaviour in patients with Crohn's disease.  Alimentary Pharmacology & Therapeutics. 2003;  17 1039-1047
• 13 Alvarez-Lobos M, Arostegui J I, Sans M. et al . Combined type-1 plasminogen activator inhibitor and NOD2/CARD15 genotyping predicts complicated Crohn's disease behaviour.  Alimentary Pharmacology & Therapeutics. 2007;  25 429-440
• 14 Fichtner-Feigl S, Fuss I J, Preiss J C, Strober W, Kitani A. Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides.  The Journal of Clinical Investigation. 2005;  115 3057-3071
• 15 Fichtner-Feigl S, Fuss I J, Young C A. et al . Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis.  J Immunol. 2007;  178 5859-5870
• 16 Lawrance I C, Wu F, Leite A Z. et al . A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B.  Gastroenterology. 2003;  125 1750-1761
• 17 Fichtner-Feigl S, Strober W, Kawakami K, Puri R K, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.  Nature Medicine. 2006;  12 99-106
• 18 Graham M F, Diegelmann R F, Elson C O. et al . Collagen content and types in the intestinal strictures of Crohn's disease.  Gastroenterology. 1988;  94 257-265
• 19 Matthes H, Herbst H, Schuppan D. et al . Cellular localization of procollagen gene transcripts in inflammatory bowel diseases.  Gastroenterology. 1992;  102 431-442
• 20 Stallmach A, Schuppan D, Riese H H, Matthes H, Riecken E O. Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn's disease.  Gastroenterology. 1992;  102 1920-1929
• 21 Dammeier J, Brauchle M, Falk W, Grotendorst G R, Werner S. Connective tissue growth factor: a novel regulator of mucosal repair and fibrosis in inflammatory bowel disease?.  The International Journal of Biochemistry & Cell Biology. 1998;  30 909-922
• 22 Pucilowska J B, McNaughton K K, Mohapatra N K. et al . IGF-I and procollagen alpha1(I) are coexpressed in a subset of mesenchymal cells in active Crohn's disease.  American Journal of Physiology. 2000;  279 G 1307-G 1322
• 23 Pucilowska J B, Williams K L, Lund P K. Fibrogenesis. IV. Fibrosis and inflammatory bowel disease: cellular mediators and animal models.  American Journal of Physiology. 2000;  279 G653-G659
• 24 Beddy D J, Watson W R, Fitzpatrick J M, O'Connell P R. Critical involvement of stress-activated mitogen-activated protein kinases in the regulation of intracellular adhesion molecule-1 in serosal fibroblasts isolated from patients with Crohn's disease.  Journal of the American College of Surgeons. 2004;  199 234-242
• 25 Brannigan A E, Watson R W, Beddy D. et al . Increased adhesion molecule expression in serosal fibroblasts isolated from patients with inflammatory bowel disease is secondary to inflammation.  Annals of Surgery. 2002;  235 507-511
• 26 Hynes R O. Integrins: versatility, modulation, and signaling in cell adhesion.  Cell. 1992;  69 11-25
• 27 Beddy D, Mulsow J, Watson R W, Fitzpatrick J M, O'Connell P R. Expression and regulation of connective tissue growth factor by transforming growth factor beta and tumour necrosis factor alpha in fibroblasts isolated from strictures in patients with Crohn's disease.  The British Journal of Surgery. 2006;  93 1290-1296
• 28 Jobson T M, Billington C K, Hall I P. Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.  The Journal of Clinical Investigation. 1998;  101 2650-2657
• 29 Simmons J G, Pucilowska J B, Keku T O, Lund P K. IGF-I and TGF-beta1 have distinct effects on phenotype and proliferation of intestinal fibroblasts.  American Journal of Physiology. 2002;  283 G 809-G 818
• 30 Vallance B A, Gunawan M I, Hewlett B. et al . TGF-beta1 gene transfer to the mouse colon leads to intestinal fibrosis.  American Journal of Physiology. 2005;  289 G 116-G 128
• 31 Blalock T D, Duncan M R, Varela J C. et al . Connective tissue growth factor expression and action in human corneal fibroblast cultures and rat corneas after photorefractive keratectomy.  Investigative Ophthalmology & Visual Science. 2003;  44 1879-1887
• 32 Crean J K, Lappin D, Godson C, Brady H R. Connective tissue growth factor: an attractive therapeutic target in fibrotic renal disease.  Expert Opin Ther Targets. 2001;  5 519-530
• 33 Denton C P, Abraham D J. Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis.  Current Opinion in Rheumatology. 2001;  13 505-511
• 34 Hayashi N, Kakimuma T, Soma Y. et al . Connective tissue growth factor is directly related to liver fibrosis.  Hepato-Gastroenterology. 2002;  49 133-135
• 35 Gao Q, Meijer M J, Kubben F J,. et al . Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases.  Dig Liver Dis. 2005;  37 584-592
• 36 Heuschkel R B, MacDonald T T, Monteleone G. et al . Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease.  Gut. 2000;  47 57-62
• 37 Louis E, Ribbens C, Godon A. et al . Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease.  Clinical and Experimental Immunology. 2000;  120 241-246
• 38 Lampe B von, Barthel B, Coupland S E, Riecken E O, Rosewicz S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory Bowel Disease.  Gut. 2000;  47 63-73
• 39 McKaig B C, McWilliams D, Watson S A, Mahida Y R. Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease.  The American Journal of Pathology. 2003;  162 1355-1360
• 40 Ma C, Chegini N. Regulation of matrix metalloproteinases (MMPs) and their tissue inhibitors in human myometrial smooth muscle cells by TGF-beta1.  Molecular Human Reproduction. 1999;  5 950-954
• 41 Ma C, Tarnuzzer R W, Chegini N. Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in mesothelial cells and their regulation by transforming growth factor-beta1.  Wound Repair Regen. 1999;  7 477-485
• 42 Bamba S, Andoh A, Yasui H. et al . Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways.  American Journal of Physiology. 2003;  285 G 529-G 538
• 43 Ferrini M G, Vernet D, Magee T R. et al . Antifibrotic role of inducible nitric oxide synthase.  Nitric Oxide. 2002;  6 283-294
• 44 Keil A, Blom I E, Goldschmeding R, Rupprecht H D. Nitric oxide down-regulates connective tissue growth factor in rat mesangial cells.  Kidney International. 2002;  62 401-411
• 45 Monteleone G, Kumberova A, Croft N M. et al . Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease.  The Journal of Clinical Investigation. 2001;  108 601-609
• 46 Stratton R, Rajkumar V, Ponticos M. et al . Prostacyclin derivatives prevent the fibrotic response to TGF-beta by inhibiting the Ras/MEK/ERK pathway.  Faseb J. 2002;  16 1949-1951
• 47 Stratton R, Shiwen X, Martini G. et al . Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients.  The Journal of Clinical Investigation. 2001;  108 241-250
• 48 Wengrower D, Zanninelli G, Pappo O. et al . Prevention of fibrosis in experimental colitis by captopril: the role of tgf-beta1.  Inflammatory Bowel Diseases. 2004;  10 536-545