Baricitinib improves the efficacy of nintedanib for the treatment of idiopathic pulmonary fibrosis

Abstract

Abstract Background: Nintedanib has been approved to treat idiopathic pulmonary fibrosis (IPF) but with limited efficacy, while targeting Janus Kinases (JAK)/ Transducer and signal activator of transcription (STAT) has emerged as a feasible strategy in this disease recently. However, the therapeutic potential of intervening in both pathways is rarely defined, prompting us to investigate combinatory effects in preclinical studies. Methods: We evaluated both the in vitro and in vivo efficacy of a drug combination, nintedanib with baricitinb, a JAK1/JAK2 inhibitor. We first examined the cell viability of single agents or combinations by the MTT assay. Then we determined the migration of the fibroblasts by a wound healing assay. Meanwhile, we quantified the protein level of related growth factor or cytokines in the cell supernatant by ELISA. We finally investigated the therapeutic potential in a bleomycin-induced mouse model. Results: Our results showed that nintedanib reduced cell viability with a mild effect in both the fibroblast cell line and the fibroblast of a patient with IPF stimulated by TGF-β or IL-6, while increasing its ability to reduce cell viability when combined with baricitinib. Nintedanib was also found to slightly reduce fibroblast migration but dramatically increase efficacy when baricitinib was added. This combinatory effect was also observed by downregulating IL-6 and TGF-β and upregulating IL-10 and IL-13 in MLE12 cells pretreated with bleomycin. In the bleomycin-induced IPF mouse model, the combination therapy increased survival rate and body weight, and reduced lung/body weight ratio compared with single agents, which moderately improved these features, respectively. In addition, both drugs improved lung functions in mice but achieved higher performance when administered together. Furthermore, histopathological improvements were also found among drug treatments, in which the combination attenuated more pulmonary inflammation and fibrosis than the single compounds. Mechanically, baricitinib orchestrated nintedanib in IPF by regulating gene expressions such as il-6, tgf-β, col1α1 and fibronectin. Conclusions: Baricitinib improves the efficacy of nintedanib by co-targeting the JAK / STAT pathway, suggesting that the drug combination can be used to therapeutically treat IPF patients.