Ruxolitinib attenuates bleomycin-induced pulmonary fibrosis in mice by modulating macrophage polarization through the JAK/STAT signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive interstitial lung disease characterized by an unclear etiology and pathogenesis. Current anti-fibrotic therapies frequently fall short in effectively halting disease progression. A critical aspect of IPF involves the role of macrophages, which exhibit distinct polarized phenotypes that significantly influence the initiation and progression of fibrosis within the lung immune microenvironment. Recent evidence highlights the importance of the JAK-STAT signaling pathway in regulating macrophage polarization, suggesting that its inhibition may offer a promising therapeutic strategy for IPF. In this study, Ruxolitinib, a JAK1/2 inhibitor that is approved for the treatment of myelofibrosis, was investigated for its effects on pulmonary fibrosis for the first time. The in vivo studies were conducted utilizing a bleomycin-induced pulmonary fibrosis model, and in vitro experiments were induced pro-inflammatory and pro-fibrotic macrophage polarization using LPS/IFN-γ and IL-4/13, respectively. Notably, our findings reveal that Ruxolitinib diminishes pro-inflammatory polarization, thereby promoting a more favorable pulmonary inflammatory microenvironment. Furthermore, Ruxolitinib inhibits fibrotic macrophage polarization, effectively curtailing myofibroblast activation and displaying clear anti-fibrotic effects. The underlying regulatory mechanism of Ruxolitinib is through inhibition of JAK1/2-mediated STAT signaling, which interrupts the pathways leading to the polarization of fibrotic macrophages and the activation of pro-inflammatory macrophages. Collectively, these results underline the potential of Ruxolitinib as a therapeutic option for IPF treatment, representing a pivotal advance in addressing a disease that has previously evaded effective pharmacological intervention.