Gastrointestinal Therapeutics

Biography

Biography: Debby Laukens

Abstract

Intestinal fibrosis is a common complication of Crohn’s disease. Fibrotic strictures are the most important indication for surgery and current therapies do not prevent their development. Due to the lack of anti-fibrotic therapeutic options, patients with a fibrostenosing phenotype (roughly 30% of cases) will progressively develop narrowing of the intestinal lumen, leading toclinically overt obstruction over time. Crohn’s-associated remodeling of the intestinal bowel wall is a complex cascade that is initiated by epithelial damage and activation of innate and adaptive effector cells, which trigger the recruitment and activation of fibroblasts that reorganize the extracellular matrix. The chronic nature of inflammation ensures sustained fibroblast activation, and together with reduced sensitivity of this fibroblast to apoptosis and their further induction by mechano transduction, this process results in disorganized, excessive extracellular matrix deposition, and finally stiffness of the bowel wall. We recently provided promising pre-clinical evidence that the inhibition of Rho kinase (ROCK), a key mediator in TGFß-induced activation of fibroblasts, harbors potent anti-fibrotic action. In spontaneous hypertensive rats, soft ROCK inhibition induced no cardiovascular effects at 10 mg/kg p.o, and daily treatment of mice did not induce toxicity. In the chronic DSS-induced model of colitis, as well as in the adoptive T cell transfer model, intestinal fibrosis develops only marginally in treated mice, which is associated with reduced colonic protein levels of pro-fibrotic cytokines IL6, IL13 and TGF1-2, andattenuated production of matrix metalloproteinases 2, 3 and 9. Both in vivo and in vitro data show decreased activation of colonic fibroblasts in the presence of ROCK inhibitors, whereas manifest autophagy is induced. Finally, we observe little or no effect of ROCK inhibition on inflammatory markers/cell activation, suggesting direct anti-fibrotic action and its use as an add-on therapy for patients who are at risk to develop stenosis.