Wouter Tobias van Haaften1, Tjasso Blokzijl2, Hendrik Sijbrand Hofker3, Peter Olinga4, Gerard Dijkstra1, Ruud A Bank5, Miriam Boersema6. 1. Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 2. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 4. Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, Groningen, 9713 AV, the Netherlands. 5. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 6. Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, the Netherlands.
Abstract
BACKGROUND AND AIMS: Crohn's disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. METHODS: Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. RESULTS: mRNA expression of collagen type I (COL1A1, 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III (COL3A1, 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. CONCLUSION: Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen.
BACKGROUND AND AIMS: Crohn's disease (CD) can be complicated by intestinal fibrosis. Pharmacological therapies against intestinal fibrosis are not available. The aim of this study was to determine whether pathways involved in collagen metabolism are upregulated in intestinal fibrosis, and to discuss which drugs might be suitable to inhibit excessive extracellular matrix formation targeting these pathways. METHODS: Human fibrotic and non-fibrotic terminal ileum was obtained from patients with CD undergoing ileocecal resection due to stenosis. Genes involved in collagen metabolism were analyzed using a microfluidic low-density TaqMan array. A literature search was performed to find potential anti-fibrotic drugs that target proteins/enzymes involved in collagen synthesis, its degradation and its recognition. RESULTS: mRNA expression of collagen type I (COL1A1, 0.76 ± 0.28 versus 37.82 ± 49.85, p = 0.02) and III (COL3A1, 2.01 ± 2.61 versus 68.65 ± 84.07, p = 0.02) was increased in fibrotic CD compared with non-fibrotic CD. mRNA expression of proteins involved in both intra- and extracellular post-translational modification of collagens (prolyl- and lysyl hydroxylases, lysyl oxidases, chaperones), collagen-degrading enzymes (MMPs and cathepsin-K), and collagen receptors were upregulated in the fibrosis-affected part. A literature search on the upregulated genes revealed several potential anti-fibrotic drugs. CONCLUSION: Expression of genes involved in collagen metabolism in intestinal fibrosis affected terminal ileum of patients with CD reveals a plethora of drug targets. Inhibition of post-translational modification and altering collagen metabolism might attenuate fibrosis formation in the intestine in CD. Which compound has the highest potential depends on a combination anti-fibrotic efficacy and safety, especially since some of the enzymes play key roles in the physiology of collagen.
Authors: Vivian Barry-Hamilton; Rhyannon Spangler; Derek Marshall; Scott McCauley; Hector M Rodriguez; Miho Oyasu; Amanda Mikels; Maria Vaysberg; Haben Ghermazien; Carol Wai; Carlos A Garcia; Arleene C Velayo; Brett Jorgensen; Donna Biermann; Daniel Tsai; Jennifer Green; Shelly Zaffryar-Eilot; Alison Holzer; Scott Ogg; Dung Thai; Gera Neufeld; Peter Van Vlasselaer; Victoria Smith Journal: Nat Med Date: 2010-09-05 Impact factor: 53.440
Authors: Lara S Kallander; David Washburn; Mark A Hilfiker; Hilary Schenck Eidam; Brian G Lawhorn; Joanne Prendergast; Ryan Fox; Sarah Dowdell; Sharada Manns; Tram Hoang; Steve Zhao; Guosen Ye; Marlys Hammond; Dennis A Holt; Theresa Roethke; Xuan Hong; Robert A Reid; Robert Gampe; Hong Zhang; Elsie Diaz; Alan R Rendina; Amy M Quinn; Bob Willette Journal: ACS Med Chem Lett Date: 2018-07-02 Impact factor: 4.345
Authors: Kandice R Levental; Hongmei Yu; Laura Kass; Johnathon N Lakins; Mikala Egeblad; Janine T Erler; Sheri F T Fong; Katalin Csiszar; Amato Giaccia; Wolfgang Weninger; Mitsuo Yamauchi; David L Gasser; Valerie M Weaver Journal: Cell Date: 2009-11-25 Impact factor: 41.582
Authors: Ganesh Raghu; Kevin K Brown; Harold R Collard; Vincent Cottin; Kevin F Gibson; Robert J Kaner; David J Lederer; Fernando J Martinez; Paul W Noble; Jin Woo Song; Athol U Wells; Timothy P M Whelan; Wim Wuyts; Emmanuel Moreau; Scott D Patterson; Victoria Smith; Selina Bayly; Jason W Chien; Qi Gong; Jenny J Zhang; Thomas G O'Riordan Journal: Lancet Respir Med Date: 2016-12-07 Impact factor: 30.700
Authors: Naoki Ikenaga; Zhen-Wei Peng; Kahini A Vaid; Susan B Liu; Shuhei Yoshida; Deanna Y Sverdlov; Amanda Mikels-Vigdal; Victoria Smith; Detlef Schuppan; Yury V Popov Journal: Gut Date: 2017-01-10 Impact factor: 23.059
Authors: Arno R Bourgonje; Marta S Alexdottir; Antonius T Otten; Roberta Loveikyte; Anne-Christine Bay-Jensen; Martin Pehrsson; Hendrik M van Dullemen; Marijn C Visschedijk; Eleonora A M Festen; Rinse K Weersma; Morten A Karsdal; Klaas Nico Faber; Joachim H Mortensen; Gerard Dijkstra Journal: Aliment Pharmacol Ther Date: 2022-06-06 Impact factor: 9.524