Abstract
Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix deposition with limited treatment options. Based on our previous observation, we hypothesized microcystin-leucine arginine (LR), an environmental cyanobacterial toxin, could potentially suppress pulmonary fibrosis. In this study, we first demonstrated that chronic exposure of microcystin-LR by oral for weeks indeed attenuated the pulmonary fibrosis both on bleomycin-induced rat and fluorescein isothiocyanate-induced mouse models. Our data further indicated that treatment with microcystin-LR substantially reduced TGF-β1/Smad signaling in rat pulmonary tissues. The experiments in vitro found that microcystin-LR was capable of blocking epithelial–mesenchymal transition (EMT) and fibroblast–myofibroblast transition (FMT) through suppressing the differentiation of CD206+ macrophages. Mechanically, microcystin-LR was found to bind to glucose-regulated protein 78 kDa (GRP78) and suppress endoplasmic reticulum unfolded protein response (UPRER) signaling pathways. These events led to the modulation of M2 polarization of macrophages, which eventually contributed to the alleviation of pulmonary fibrosis. Our results revealed a novel mechanism that may account for therapeutic effect of microcystin-LR on IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF), a disease of unknown etiology, is characterized by chronic inflammation, myofibroblast proliferation and exaggerated extracellular matrix (ECM) accumulation, which leads to a progressive decline of lung function with limited therapeutic options[1,2,3,4]
To investigate the possible effect of microcystin-leucine arginine (LR) on progressive fibrosis, we exposed rats to microcystin-LR through drinking water starting on days 7 (LR7), 14 (LR14) or 28 (LR28) after intratracheal administration of bleomycin, corresponding to the early phase, transitional phase of inflammation/fibrosis, and the late stage with increased deposition of lung collagen, respectively (Fig. 1a)
We conceived this study based on our previous observation of a reduced expression of TGF-β1 in mouse lung tissues after chronic exposure to microcystin-LR
Summary
Idiopathic pulmonary fibrosis (IPF), a disease of unknown etiology, is characterized by chronic inflammation, myofibroblast proliferation and exaggerated extracellular matrix (ECM) accumulation, which leads to a progressive decline of lung function with limited therapeutic options[1,2,3,4]. The pathogenesis of IPF is currently assumed to be the recurrent or persistent microinjuries to the pulmonary alveolus, which drives microenvironmental changes and provokes a dysregulated tissue repair process[5,6,7]. The alternatively activated macrophages can trigger a pathologic fibrotic-repair mechanism if this irritant persists[11,12,13]. The pro-fibrotic roles of alternatively activated macrophages are mainly associated with recruitment and proliferation of fibroblasts, and induction of epithelial to mesenchymal transition (EMT) and fibroblast to myofibroblast transition (FMT) through the secretion of fibrogenic mediators, in particular TGFβ114,15. Myofibroblasts are widely believed as the principal effector cells responsible for fibrosis
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