Abstract
Systemic sclerosis (SSc) is a connective tissue disease that often causes pulmonary fibrosis. Dipeptidyl peptidase 4 (DPP4) inhibitor has shown anti-fibrotic properties in various fibrotic diseases. However, only two studies have reported its anti-fibrosis effects in pulmonary fibrosis, and the mechanism is not completely clear. In the present study, we further investigated the protective effects of linagliptin, a highly specific DPP4 inhibitor, on pulmonary fibrosis in SSc mouse model and the potential mechanisms. The results showed that linagliptin ameliorated pulmonary fibrosis in SSc mouse model, as evidenced by improved pathological changes of lung and body weight loss induced by BLM. Linagliptin also reduced BLM-induced oxidative stress, inflammation in lung in vivo. We revealed that linagliptin attenuated BLM-induced endothelial-to-mesenchymal transition (EndMT) in vitro and in vivo. BLM-induced enhanced migration ability of endothelial cells was also alleviated by linagliptin. Moreover, we confirmed that the Akt/mammalian target of rapamycin pathway was involved in BLM-induced EndMT in vivo, which was suppressed by linagliptin. In summary, we further confirmed the therapeutic effects of linagliptin on pulmonary fibrosis in SSc mouse model, which is based on its inhibitory effects on EndMT, oxidative stress, and inflammation.
Highlights
Systemic sclerosis (SSc), a rare autoimmune-mediated connective tissue disease often causes progressive pulmonary fobrosis [1], which causes a high mortality [2]
We further investigated the protective effects of linagliptin, a highly specific Dipeptidyl peptidase 4 (DPP4) inhibitor, on pulmonary fibrosis in SSc mouse model and the potential mechanisms
We further confirmed the therapeutic effects of linagliptin on pulmonary fibrosis in SSc mouse model, which is based on its inhibitory effects on endothelial to mesenchymal transition (EndMT), oxidative stress and inflammation
Summary
Systemic sclerosis (SSc), a rare autoimmune-mediated connective tissue disease often causes progressive pulmonary fobrosis [1], which causes a high mortality [2]. A previous study has reported that pulmonary fibrosis or interstitial lung disease is present in 80% of patients with SSc [3]. Treatment for SSc-related pulmonary fibrosis is limited. The pathogenesis of SSc-related pulmonary fibrosis is complicated and poor understanding. Myofibroblasts, an unique population of mesenchymal cells, play a pivotal role in the pathogenesis of fibrotic diseases. The process has been demonstrated to be involved in the progression of various fibrotic diseases [6, 7, 8], as well as SSc-related pulmonary fibrosis [9]. Given the critical role of myofibroblasts in the pathogenesis of SSc, treatments targeting EndMT are promising therapies
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