Regulation of the intestinal smooth muscle cell phenotype by the antifibrotic drug nintedanib
The phenotype of the intestinal smooth muscle cell (ISMC) is typically contractile and non- proliferative, but this can be modulated to allow for proliferation as a wound repair mechanism. While phenotypic modulation of ISMC is normal, chronic inflammation causes excessive proliferation of ISMC, which can contribute to the pathophysiology of inflammatory bowel diseases (IBD). Particularly, in Crohn’s disease (CD), as a consequence of ISMC hyperplasia and extracellular matrix (ECM) collagen deposition, intestinal strictures may arise, ultimately leading to obstruction. Since there are minimal effective treatment options for intestinal strictures, we explored the effects of a multimodal tyrosine kinase inhibitor, nintedanib (NIND), which was recently approved for idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung condition resembling CD. High-passage adult rat ISMC were used in vitro as a model system to study the growth and phenotypic changes that occur in the inflamed intestine. NIND successfully suppressed growth of ISMC but was ineffective against intestinal epithelial cells (IEC), showing selectivity towards cells of the mesenchymal origin. Interestingly, NIND showed protracted inhibition of growth, and pretreated cells grew at a slower rate after subculturing, suggesting heritable effects. Additionally, NIND induced collagen secretion in ISMC, showing that its multimodal capabilities can contribute to wound repair. Further, NIND treatment upregulated smooth muscle contractile marker expression in high-passage ISMC. Finally, and importantly, we showed that the proinflammatory cytokines, IL1β/TNFα, stimulate cytokine production in ISMC, causing a positive feedback loop, and this can be controlled with NIND treatment. Overall, these findings provide evidence that NIND controls the phenotype of ISMC, and because these changes are heritable, the effects of NIND may be associated with epigenetic changes. The effect of NIND on ISMC elucidates its role as a therapy for intestinal strictures, through restoring contractility, and improving intestinal motility.