Targeted Inhibition of ROCK Specifically in the Polarization Interstitial Macrophages Suppresses Pulmonary Fibrosis

Abstract Background Pulmonary fibrosis (PF) is a kind of progressive interstitial lung disease with no effective therapy. Rho/ROCK pathway has been confirmed to be activated in the process of PF in bleomycin-induced mice model in previous studies, which is involved in cell proliferation, tissue repair and regeneration. Bleomycin-induced and radiation-induced pulmonary fibrosis mice models were used to explore the effects and mechanism of WXWHO265, a novel unselected ROCK inhibitor, in PF.Methods The bleomycin-induced mice models were constructed by intratracheal instillation. The radiation-induced mice model were established by bilateral thoracic irradiation. Intragastric administration was applied to the WXWHO265 treated groups one day after model established. Flow cytometry, qRT-PCR, HE staining, Masson staining, and immunohistochemistry (IHC) analysis were used for further investigation.ResultsIn both types of PF models, the fibrosis in the lung was severe and became worse as time progressed. The status of mice in WXWHO265 treated groups was better than control group (saline treated group). The proportion of M2 macrophages in the lung tissue of bleomycin-induced group significantly increased compared to control group. The proportion of M2 macrophage of day 28 was higher than day 14 and day 7 in both PF models. The proportions of M2 macrophage in WXWHO265 high dose group(25mg/kg) and control group were statistically different (p<0.05). The p-STAT3 in lung tissue was significantly decreased in the day 28 in PF models. In vitro macrophages polarization experiment, the macrophages transformed into M2 macrophages by IL-4 stimulating. The proportion of M2 macrophages decreased after treated with WXWHO265. ConclusionsInhibiting ROCK could significant ameliorate PF in mice model by regulating the polarization of interstitial macrophages. Furthermore, the results showed that ROCK regulated the polarization of M2 macrophages by mediating the phosphorylation of STAT3, which might be a potential target in treating PF.