Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial pneumonia with high mortality. Melatonin, a hormone predominantly secreted by the pineal gland, has been reported to participate in the process of IPF. However, the mechanisms underlying the effect of melatonin in pulmonary fibrosis have not been elucidated to date. This study was designed to evaluate the anti-fibrotic role of melatonin in pulmonary fibrosis and to elucidate the potential mechanisms. We observed that melatonin markedly attenuated bleomycin (BLM)-induced experimental lung fibrosis in mice and inhibited TGF-β1-induced fibrogenesis in lung fibroblasts. Additionally, we determined that luzindole, a melatonin receptor inhibitor, reduced the anti-fibrotic effect of melatonin. Further studies showed that melatonin alleviated the translocation of YAP1 from cytoplasm to nucleus, a key downstream effector of the Hippo pathway, in vivo and in vitro by interacting with its receptor. Taken together, our results suggest that melatonin prevents lung fibrosis by inhibiting YAP1 and indicate that melatonin replacement could be a novel strategy for the treatment of lung fibrosis.
Highlights
Idiopathic pulmonary fibrosis displays a condition in which the natural lung biological makeup is replaced by progress of lung structure aberrant remodeling, abundant accumulation of extracellular matrix and dramatic changes in the cell phenotype of both fibroblasts and alveolar epithelial cells [1]
We characterized the inhibitory effect of melatonin in BLM-induced pulmonary fibrosis and clarified the potent molecular mechanisms to provide an ideal explanation of this effect
Melatonin alleviated lung fibrosis in vivo and in vitro by binding to its receptor, and this anti-fibrotic effect was mitigated by up-regulation and functional activation of YAP1 (Figure 6D)
Summary
Idiopathic pulmonary fibrosis displays a condition in which the natural lung biological makeup is replaced by progress of lung structure aberrant remodeling, abundant accumulation of extracellular matrix and dramatic changes in the cell phenotype of both fibroblasts and alveolar epithelial cells [1]. The functional effect of melatonin involves a wide spectrum of pathophysiological processes, including delaying senescence [5], anti-tumorigenesis [6], sleep melioration [7] and immune adjustment [8]. Growing evidence suggests that melatonin exerts anti-fibrotic effects in the heart, kidney, lung, liver and other organs [4]. During the pathogenesis of fibrosis, melatonin plays a protective role in initial injury to the organ, activation of effector cells (fibroblasts, myofibroblasts, and inflammatory cells), and accumulation of ECM. An increasing number of studies have revealed the significant role of melatonin in the pathophysiological processes of pulmonary fibrosis, an exhaustive examination of the detailed mechanisms has not been presented
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