Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo

Chronic inflammation of the human intestine in Crohn's disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-R beta or NF kappa B but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1 beta and TNF alpha, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNF alpha and IL-1 beta, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.

Automated summary

Recent studies have shown that the tyrosine kinase inhibitor nintedanib (NIN) can inhibit hyperplasia of intestinal smooth muscle cells (ISMC) in Crohn's disease (CD) and similar pathologies, reducing the expression of inflammatory cytokines.