Crizotinib attenuates bleomycin-induced pulmonary fibrosis via regulating fibroblast activation

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease. Crizotinib is an oral tyrosine kinase inhibitor (TKI), which has been widely used in the treatment of non-small cell lung cancer (NSCLC). Previous studies have demonstrated that crizotinib can inhibit downstream signaling pathways of anaplastic lymphoma kinase (ALK) in lung adenocarcinoma mouse, including pSTAT3, pAKT, and pERK, which also play an important role in the development and progression of pulmonary fibrosis. We conducted this study to investigate the antifibrotic efficacy of crizotinib in pulmonary fibrosis in vivo and in vitro, as well as exploring the potential mechanism further.

Fibroblasts were stimulated with TGF-β1 and co-treated with crizotinib to evaluate its impact on fibroblast activation markers as well as main related proteins of signal pathways in vitro. Male C57BL/6 mice were administered bleomycin (BLM) established as in vivo model. We assessed lung function, micro-computed tomography (CT), hydroxyproline level, percentage of fibrotic areas and the expression of fibrotic factors to evaluate the effects of crizotinib on pulmonary fibrosis. Western blot was performed to identify our speculated hypothesis.

In vitro studies showed that crizotinib reduced the gene and protein expression levels of the fibronectin (Fn), Collagen 1 (Col-1) and α-smooth muscle actin (α-SMA), as well as exerting potential anti-fibrotic effects by inhibiting the activation and migration of fibroblasts. Additionally, the results of the in vivo studies demonstrated that crizotinib could improve lung dysfunction, pulmonary fibrosis lesions, area of full ventilation in CT, and the expression of fibrotic-associated factors in lung tissues of BLM-mice. Additionally, crizotinib inhibited the PI3K/AKT/mTOR, STAT3 and ERK signaling pathways, which play vital roles during pulmonary fibrosis.

Through suppressing fibroblast proliferation and activation, crizotinib could alleviate pulmonary fibrosis in BLM induced mice. Crizotinib could inhibit the PI3K/AKT/mTOR, STAT3 and ERK signaling pathways. Crizotinib might be an emerging medication choice for patients with IPF.