Therapeutic Targeting of Intestinal Fibrosis in Crohn’s Disease: Comparison
Please note this is a comparison between Version 3 by Lindsay Dong and Version 2 by Lindsay Dong.

Intestinal fibrosis is one of the most threatening complications of Crohn’s disease. Endoscopic and surgical approaches are currently the only options available and there is an urgent need for targeted anti-fibrotic therapy. Several molecules investigated in preclinical studies, which are awaiting clinical trials in humans, have proven effective in CD stricturing phenotype and may be available in the near future as additional weapons in preventing or reversing intestinal fibrosis. 

  • antifibrotic therapy
  • Crohn’s disease
  • IBD
  • intestinal fibrosis
Please wait, diff process is still running!

References

  1. Baumgart, D.C.; Sandborn, W.J. Chron’s disease. Lancet 2012, 380, 1590–1605.
  2. Kaplan, G. The global burden of IBD: From 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 720–727.
  3. Di Sabatino, A.; Rovedatti, L. Recent advances in understanding Crohn’s disease. Intern. Emerg. Med. 2013, 8, 101–113.
  4. Knowles, S.R.; Graff, L.A. Quality of life in inflammatory bowel disease: A systematic review and meta-analyses-Part I. Inflamm. Bowel Dis. 2018, 24, 742–751.
  5. Rieder, F.; Fiocchi, C. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases. Gastroenterology 2017, 152, 340–350.
  6. Rieder, F.; Bettenworth, D. An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn’s disease. Aliment Pharmacol. Ther. 2018, 48, 347–357.
  7. Shaw, T.J.; Martin, P. Wound repair at a glance. J. Cell Sci. 2009, 122, 3209–3213.
  8. Xue, M.; Jackson, C.J. Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring. Adv. Wound Care 2015, 4, 119–136.
  9. Pakshir, P.; Boris, H. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. J. Int. Soc. Matrix Biol. 2018, 68-69, 81–93.
  10. Lenti, M.V.; Di Sabatino, A. Intestinal fibrosis. Mol. Aspects Med. 2019, 65, 100–109.
  11. Medina, C.; Santos-Martinez, M.J. Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis. J. Pathol. 2011, 224, 461–472.
  12. Chen, W.; Lu, C. Smooth muscle hyperplasia/hypertrophy is the most prominent histological change in Crohn’s fibrostenosing bowel strictures: A semiquantitative analysis by using a novel histological grading scheme. J. Crohn’s Colitis 2017, 11, 92–104.
  13. Rieder, F.; Fiocchi, C. Intestinal fibrosis in IBD-a dynamic, multifactorial process. Nat. Rev. Gastroenterol. Hepatol. 2009, 6, 228–235.
  14. Speca, S.; Giusti, I. Cellular and molecular mechanisms of intestinal fibrosis. World J. Gastroenterol. 2012, 18, 3635–3661.
  15. Jiang, H.; Shen, J. Epithelial-mesenchymal transition in Crohn’s disease. Mucosal Immunol. 2018, 11, 294–303.
  16. Rieder, F.; Kessler, S.P. Inflammation-induced endothelial-to-mesenchymal transition: A novel mechanism of intestinal fibrosis. Am. J. Pathol. 2011, 179, 2660–2673.
  17. Di Sabatino, A.; Jackson, C.L. Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn’s disease strictures. Gut 2009, 58, 777–789.
  18. Dinarello, C.A. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol. Rev. 2018, 281, 8–27.
  19. Drygiannakis, I.; Valatas, V. Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: Implication in intestinal fibrosis. J. Crohn’s Colitis 2013, 7, 286–300.
  20. Lopetuso, L.R.; Scaldaferri, F. Emerging role of the interleukin (IL)-33/ST2 axis in gut mucosal wound healing and fibrosis. Fibrogenesis Tissue Repair. 2012, 5, 18.
  21. Elias, M.; Zhao, S. IL-36 in chronic inflammation and fibrosis—bridging the gap? J. Clin. Investig. 2021, 131, e144336.
  22. Tindemans, I.; Joose, M.E. Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020, 9, 110.
  23. Friedrich, M.; Pohin, M. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019, 50, 992–1006.
  24. Latella, G.; Viscido, A. Controversial Contribution of Th17/IL-17 Toward the Immune Response in Intestinal Fibrosis. Dig. Dis. Sci. 2020, 65, 1299–1306.
  25. Biancheri, P.; Pender, S.L. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013, 6, 13.
  26. Fina, D.; Franzè, E. Interleukin-25 production is differently regulated by TNF-α and TGF-β1 in the human gut. Mucosal. Immunol. 2011, 4, 239–244.
  27. Rovedatti, L.; Di Sabatino, A. Fibroblast activation protein expression in Crohn’s disease strictures. Inflamm. Bowel Dis. 2011, 17, 1251–1253.
  28. Truffi, M.; Sorrentino, L. Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn’s Disease Strictures Ex Vivo. Inflamm. Bowel Dis. 2018, 24, 332–345.
  29. Di Sabatino, A.; Ciccocioppo, R. Serum bFGF and VEGF correlate respectively with bowel wall thickness and intramural blood flow in Crohn’s disease. Inflamm. Bowel Dis. 2004, 10, 573–577.
  30. Shih, D.Q.; Zheng, L. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 2014, 7, 1492–1503.
  31. Barrett, R.; Zhang, X. Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am. J. Pathol. 2012, 180, 636–649.
  32. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 2018, 18, 134–147.
  33. Chrysanthopoulou, A.; Mitroulis, I. Neutrophil extracellular traps promote differentiation and function of fibroblasts. J. Pathol. 2014, 233, 294–307.
  34. Dragoni, G.; De Hertogh, G. The Role of Citrullination in Inflammatory Bowel Disease: A Neglected Player in Triggering Inflammation and Fibrosis? Inflamm. Bowel Dis. 2021, 27, 134–144.
  35. Voglova, K.; Bezakova, J. Micro RNAs: An arguable appraisal in medicine. Endocr. Regul. 2016, 50, 106–124.
  36. Nijhuis, A.; Biancheri, P. In Crohn’s disease fibrosis-reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts. Clin. Sci. 2014, 127, 341–350.
  37. Mongroo, P.S.; Rustgi, A.K. The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol. Ther. 2010, 10, 219–222.
  38. Chen, Y.; Ge, W. miR-200b is involved in intestinal fibrosis of Crohn’s disease. Int. J. Mol. Med. 2012, 29, 601–606.
  39. Nishida, A.; Inoue, R. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin. J. Gastroenterol. 2018, 11, 1–10.
  40. Rieder, F. The gut microbiome in intestinal fibrosis: Environmental protector or provocateur? Sci. Transl. Med. 2013, 5, 1–90.
  41. Rieder, F.; Bhilocha, S. Activation of toll-like receptor (TLR) 5 induces a pro-fibrogenic phenotype on human intestinal myofibroblasts (HIF)—A novel pathway mediated by Caspase 1. Gastroenterology 2011, 140, S114.
  42. Imai, J.; Kitamoto, S. Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis. Mucosal Immunol. 2019, 12, 632–643.
  43. Abreu, M.T.; Taylor, K.D. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 2002, 123, 679–688.
  44. Grassl, G.A.; Valdez, Y. Chronic enteric salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology 2008, 134, 768–780.
  45. Mourelle, M.; Salas, A. Stimulation of transforming growth factor beta1 by enteric bacteria in the pathogenesis of rat intestinal fibrosis. Gastroenterology 1998, 114, 519–526.
  46. Wells, R.G. The role of matrix stiffness in regulating cell behavior. Hepatology 2008, 47, 1394–1400.
  47. Johnson, L.A.; Rodansky, E.S. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm. Bowel Dis. 2013, 19, 891–903.
  48. Johnson, L.A.; Luke, A. Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: Impact of a "Top-Down" approach to intestinal fibrosis in mice. Inflamm. Bowel Dis. 2012, 18, 460–471.
  49. Peyrin-Biroulet, L.; Chamaillard, M. Mesenteric fat in Crohn’s disease: A pathogenetic hallmark or an innocent bystander? Gut 2007, 56, 577–583.
  50. Kredel, L.I.; Batra, A. Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut 2013, 62, 852–862.
  51. Mao, R.; Kurada, S. The Mesenteric Fat and Intestinal Muscle Interface: Creeping Fat Influencing Stricture Formation in Crohn’s Disease. Inflamm. Bowel Dis. 2019, 25, 421–426.
  52. Lu, C.; Baraty, B. Systematic review: Medical therapy for fibrostenosing Crohn’s disease. Aliment Pharmacol. Ther. 2020, 51, 1233–1246.
  53. Yaffe, B.H.; Korelitz, B.I. Prognosis for nonoperative management of small-bowel obstruction in Crohn’s disease. J. Clin. Gastroenterol. 1983, 5, 211–215.
  54. Vasilopoulos, S.; Kugathasan, S. Intestinal strictures complicating initially successful infliximab treatment for luminal Crohn’s disease. Am. J. Gastroenterol. 2000, 95, 2503.
  55. Toy, L.S.; Scherl, E.J. Complete bowel obstruction following initial response to infliximab therapy for Crohn’s disease: A series of a newly described complication. Gastroenterology 2000, 118, A569.
  56. Allocca, M.; Bonifacio, C. Efficacy of tumour necrosis factor antagonists in stricturing Crohn’s disease: A tertiary center real-life experience. Dig. Liver Dis. 2017, 49, 872–877.
  57. Hanauer, S.B.; Feagan, B.G. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002, 359, 1541–1549.
  58. Bouhnik, Y.; Carbonnel, F. Efficacy of adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: A multicentre, prospective, observational cohort (CREOLE) study. Gut 2018, 67, 53–60.
  59. Engel, T.; Ungar, B. Vedolizumab in IBD-Lessons from Real-world Experience; A Systematic Review and Pooled Analysis. J. Crohn’s Colitis 2018, 12, 245–257.
  60. Ma, C.; Fedorak, R.N. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn’s disease: Real world experience from a multicentre cohort. Aliment Pharmacol. Ther. 2017, 45, 1232–1243.
  61. Gordon, M. 5-Aminosalicylates to maintain remission in Crohn’s disease: Interpreting conflicting systematic review evidence. World J. Gastrointest. Pharmacol. Ther. 2017, 8, 99–102.
  62. Rieder, F.; Latella, G. European Crohn’s and Colitis Organisation Topical Review on Prediction, Diagnosis and Management of Fibrostenosing Crohn’s Disease. J. Crohns Colitis 2016, 10, 873–885.
  63. Hirai, F.; Andoh, A. Efficacy of Endoscopic Balloon Dilation for Small Bowel Strictures in Patients With Crohn’s Disease: A Nationwide, Multi-centre, Open-label, Prospective Cohort Study. J. Crohns Colitis 2018, 12, 394–401.
  64. Bettenworth, D.; Gustavsson, A. A Pooled Analysis of Efficacy, Safety, and Long-term Outcome of Endoscopic Balloon Dilation Therapy for Patients with Stricturing Crohn’s Disease. Inflamm. Bowel Dis. 2017, 23, 133–142.
  65. Siddiqui, U.D.; Banerjee, S. Tools for endoscopic stricture dilation. Gastrointest. Endosc. 2013, 78, 391–404.
  66. Bemelman, W.A.; Warusavitarne, J. ECCO-ESCP Consensus on Surgery for Crohn’s Disease. J. Crohns Colitis 2018, 12, 1–16.
  67. Katsuno, H.; Maeda, K. Novel antimesenteric functional end-to-end handsewn (Kono-S) anastomoses for Crohn’s disease: A report of surgical procedure and short-term outcomes. Dig. Surg. 2015, 32, 39–44.
  68. Coffey, C.J.; Kiernan, M.G. Inclusion of the Mesentery in Ileocolic Resection for Crohn’s Disease is Associated with Reduced Surgical Recurrence. J. Crohns Colitis 2018, 12, 1139–1150.
  69. Sica, G.S.; Iaculli, E. Laparoscopic versus open ileo-colonic resection in Crohn’s disease: Short-and long-term results from a prospective longitudinal study. J. Gastrointest. Surg. 2008, 12, 1094–1102.
  70. Campbell, S.E.; Katwa, L.C. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J. Mol. Cell Cardiol. 1997, 29, 1947–1958.
  71. Warner, F.J.; Lubel, J.S. Liver fibrosis: A balance of ACEs? Clin. Sci. 2007, 113, 109–118.
  72. Uhal, B.D.; Kim, J.K. Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: Autocrine mechanisms in myofibroblasts and macrophages. Curr. Pharm. Des. 2007, 13, 1247–1256.
  73. Jaszewski, R.; Tolia, V. Increased colonic mucosal angiotensin I and II concentrations in Crohn’s colitis. Gastroenterology 1990, 98, 1543–1548.
  74. Wengrower, D.; Zanninelli, G. Prevention of fibrosis in experimental colitis by captopril: The role of tgf-beta1. Inflamm. Bowel Dis. 2004, 10, 536–545.
  75. Koga, H.; Yang, H. Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: Development of a unique mode of treatment. Surgery 2008, 144, 259–268.
  76. Wengrower, D.; Zanninelli, G. Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats. Can. J. Gastroenterol. 2012, 26, 33–39.
  77. Wei, J.; Ghosh, A.K. PPARγ downregulation by TGFß in fibroblast and impaired expression and function in systemic sclerosis: A novel mechanism for progressive fibrogenesis. PLoS ONE 2010, 5, e13778.
  78. Ghosh, A.K.; Bhattacharyya, S. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator. FASEB J. 2009, 23, 2968–2977.
  79. Speca, S.; Rousseaux, C. Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis. Inflamm. Bowel Dis. 2016, 22, 279–292.
  80. Koo, J.B.; Nam, M.O. Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts. BMC Gastroenterol. 2017, 17, 73.
  81. Bourgier, C.; Haydont, V. Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut 2005, 54, 336–343.
  82. Sandbo, N.; Kregel, S. Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGF-beta. Am. J. Respir. Cell Mol. Biol. 2009, 41, 332–338.
  83. Johnson, L.A.; Rodansky, E.S. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β-induced fibrogenesis in human colonic myofibroblasts. Inflamm. Bowel Dis. 2014, 20, 154–165.
  84. Bian, H.; Zhou, Y. Rho-kinase signaling pathway promotes the expression of PARP to accelerate cardiomyocyte apoptosis in ischemia/reperfusion. Mol. Med. Rep. 2017, 16, 2002–2008.
  85. Holvoet, T.; Devriese, S. Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor. Gastroenterology 2017, 153, 1054–1067.
  86. Li, C.; Flynn, R.S. Increased activation of latent TGF-β1 by αVβ3 in human Crohn’s disease and fibrosis in TNBS colitis can be prevented by cilengitide. Inflamm. Bowel Dis. 2013, 19, 2829–2839.
  87. Sathiyamoorthy, G.; Sehgal, S. Pirfenidone and Nintedanib for Treatment of Idiopathic Pulmonary Fibrosis. South Med. J. 2017, 110, 393–398.
  88. Ma, C.; Jairath, V. Targeting anti-fibrotic pathways in Crohn’s disease—The final frontier? Best Pract. Res. Clin. Gastroenterol. 2019, 38-39, 101603.
  89. Cui, Y.; Zhang, M. Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells. 2020, 9, 775.
  90. Sun, Y.; Zhang, Y. Pirfenidone suppresses TGF-β1-induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway. Mol. Med. Rep. 2018, 18, 3907–3913.
  91. Li, G.; Ren, J. Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-β signaling in a murine colitis model. Biochem. Pharmacol. 2016, 117, 57–67.
  92. Sun, Y.W.; Zhang, Y.Y. Pirfenidone prevents radiation-induced intestinal fibrosis in rats by inhibiting fibroblast proliferation and differentiation and suppressing the TGF-β1/Smad/CTGF signaling pathway. Eur. J. Pharmacol. 2018, 822, 199–206.
  93. Latella, G.; Viscido, A. Could Pirfenidone Also be Effective in Treating Intestinal Fibrosis? Cells 2020, 9, 1762.
  94. Wang, R.; Wang, D. Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis. Front. Immunol. 2021, 12, 670159.
  95. Zhu, Z.; Li, M.; Shu, X. Thalidomide is a therapeutic agent that is effective in inducing and maintaining endoscopic remission in adult CD patients. Clin. Res. Hepatol. Gastroenterol. 2017, 41, 210–216.
  96. Chen, H.; Xu, H. Thalidomide Prevented and Ameliorated Pathogenesis of Crohn’s Disease in Mice via Regulation of Inflammatory Response and Fibrosis. Front. Pharmacol. 2019, 10, 1486.
  97. Chu, S.J.; Zhang, Z.H. Effect of bevacizumab on the expression of fibrosis-related inflammatory mediators in ARPE-19 cells. Int. J. Ophthalmol. 2017, 10, 366–371.
  98. Alkim, C.; Alkim, H. Angiogenesis in Inflammatory Bowel Disease. Int. J. Inflam. 2015, 2015, 970890.
  99. Juillerat-Jeanneret, L.; Gerber-Lemaire, S. The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders. Mini Rev. Med. Chem. 2009, 9, 215–226.
  100. Egger, C.; Cannet, C. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur. J. Pharmacol. 2017, 809, 64–72.
  101. Hill, C.; Li, J. Autophagy inhibition-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell Death Dis. 2019, 10, 591.
  102. Yao, L.; Conforti, F. Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis. Cell Death Differ. 2019, 26, 943–957.
  103. Zeisberg, M.; Yang, C. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 2007, 282, 23337–23347.
  104. Zeisberg, E.M.; Tarnavski, O. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 2007, 13, 952–961.
  105. Zeisberg, M.; Hanai, J. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 2003, 9, 964–968.
  106. Flier, S.N.; Tanjore, H. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J. Biol. Chem. 2010, 285, 20202–20212.
  107. Yang, J.; Zhou, C.Z. miR-200b-containing microvesicles attenuate experimental colitis associated intestinal fibrosis by inhibiting epithelial-mesenchymal transition. J. Gastroenterol. Hepatol. 2017, 32, 1966–1974.
  108. Muccioli, G.G. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov. Today 2010, 15, 474–483.
  109. Petrosino, S.; Ligresti, A. Endocannabinoid chemical biology: A tool for the development of novel therapies. Curr. Opin. Chem. Biol. 2009, 13, 309–320.
  110. Izzo, A.A.; Camilleri, M. Emerging role of cannabinoids in gastrointestinal and liver diseases: Basic and clinical aspects. Gut 2008, 57, 1140–1155.
  111. Julien, B.; Grenard, P. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005, 128, 742–755.
  112. Di Sabatino, A.; Battista, N. The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol. 2011, 4, 574–583.
  113. Li, J.; Liu, L. Role of Interleukin-17 in Pathogenesis of Intestinal Fibrosis in Mice. Dig. Dis. Sci. 2020, 65, 1971–1979.
  114. Paul, J.; Singh, A.K. IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5. Mucosal Immunol. 2018, 11, 427–436.
  115. Hueber, W.; Sands, B.E. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: Unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012, 61, 1693–1700.
  116. Targan, S.R.; Feagan, B. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn’s Disease. Am. J. Gastroenterol. 2016, 111, 1599–1607.
  117. Zhang, B.L.; Liang, T.S. Interleukin-17 as a Therapy Target in Intestinal Fibrosis. Dig. Dis. Sci. 2020, 65, 3054–3055.
  118. Melton, E.; Qiu, H. Interleukin-36 Cytokine/Receptor Signaling: A New Target for Tissue Fibrosis. Int. J. Mol. Sci. 2020, 21, 6458.
  119. Scheibe, K.; Kersten, C. Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation. Gastroenterology 2019, 156, 1082–1097.
  120. Danese, S.; Klopocka, M. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin. Gastroenterol. Hepatol. 2021, 19, 2324–2332.
  121. Fleischmann, R.M.; Wagner, F. Safety, Tolerability, and Pharmacodynamics of ABT-122, a Tumor Necrosis Factor- and Interleukin-17-Targeted Dual Variable Domain Immunoglobulin, in Patients with Rheumatoid Arthritis. Arthritis Rheumatol. 2017, 69, 2283–2291.
  122. Mease, P.J.; Genovese, M.C. Phase II Study of ABT-122, a Tumor Necrosis Factor- and Interleukin-17A-Targeted Dual Variable Domain Immunoglobulin, in Patients with Psoriatic Arthritis with an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2018, 70, 1778–1789.
  123. Baker, K.F.; Isaacs, J.D. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. 2018, 77, 175–187.
  124. Bárcena, C.; Stefanovic, M. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J. Hepatol. 2015, 63, 670–678.
  125. Steiner, C.A.; Rodansky, E.S. AXL Is a Potential Target for the Treatment of Intestinal Fibrosis. Inflamm. Bowel Dis. 2021, 27, 303–316.
  126. Gottlieb, Y.; Elhasid, R. Neutrophil extracellular traps in pediatric inflammatory bowel disease. Pathol. Int. 2018, 68, 517–523.
  127. He, Z.; Si, Y. Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease. Thromb. Haemost. 2016, 115, 738–751.
  128. Angelidou, I.; Chrysanthopoulou, A. REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1β Inflammatory Response in Active Ulcerative Colitis. J. Immunol. 2018, 200, 3950–3961.
  129. Dinallo, V.; Marafini, I. Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis. J. Crohn’s Colitis 2019, 13, 772–784.
  130. Suzuki, M.; Ikari, J. PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung. Am. J. Respir. Cell Mol. Biol. 2020, 63, 806–818.
  131. de Bruyn, J.R.; van den Brink, G.R. Fibrostenotic Phenotype of Myofibroblasts in Crohn’s Disease is Dependent on Tissue Stiffness and Reversed by LOX Inhibition. J. Crohn’s Colitis 2018, 12, 849–859.
  132. Kashima, S.; Fujiya, M. Polyphosphate, an active molecule derived from probiotic Lactobacillus brevis, improves the fibrosis in murine colitis. Transl. Res. 2015, 166, 163–175.
  133. Park, J.S.; Choi, J. A probiotic complex, rosavin, zinc, and prebiotics ameliorate intestinal inflammation in an acute colitis mouse model. J. Transl. Med. 2018, 16, 37.
  134. Liu, M.; Zhang, X. Protective effects of a novel probiotic strain, Lactococcus lactis ML2018, in colitis: In vivo and in vitro evidence. Food Funct. 2019, 10, 1132–1145.
  135. Deng, X.; Zheng, C. Treatment with a probiotic combination reduces abdominal adhesion in rats by decreasing intestinal inflammation and restoring microbial composition. Oncol. Rep. 2020, 43, 986–998.
  136. Lombardi, F.; Augello, F.R. Soluble Fraction from Lysate of a High Concentration Multi-Strain Probiotic Formulation Inhibits TGF-β1-Induced Intestinal Fibrosis on CCD-18Co Cells. Nutrients 2021, 13, 882.
  137. Schuppan, D.; Pinzani, M. Anti-fibrotic therapy: Lost in translation? J. Hepatol. 2012, 56, S66–S74.
  138. Chen, Y.; Lin, Y. Robust bioengineered 3D functional human intestinal epithelium. Sci. Rep. 2015, 5, 13708.
  139. Giuffrida, P.; Curti, M. Decellularized Human Gut as a Natural 3D Platform for Research in Intestinal Fibrosis. Inflamm. Bowel Dis. 2019, 25, 1740–1750.
  140. Giuffrida, P.; Pinzani, M. Biomarkers of intestinal fibrosis—One step towards clinical trials for stricturing inflammatory bowel disease. United Eur. Gastroenterol J. 2016, 4, 523–530.
  141. Steiner, C.A.; Berinstein, J.A. Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn’s Disease: A Systematic Review. Clin. Gastroenterol. Hepatol. 2021, 21, S1542–S3565.
  142. Danese, S.; Bonovas, S. Identification of Endpoints for Development of Antifibrosis Drugs for Treatment of Crohn’s Disease. Gastroenterology 2018, 155, 76–87.
More
Video Production Service