Dioscin Alleviates Crystalline Silica-Induced Pulmonary Inflammation and Fibrosis through Promoting Alveolar Macrophage Autophagy

Abstract

Occupational exposure to crystalline silica (CS) particles leads to silicosis, which is characterized by chronic inflammation and abnormal tissue repair. Alveolar macrophages (AMs) play a crucial role in the process of silicosis. Previously, we demonstrated positive effect of dioscin on silicosis through modulating macrophage-elicited innate immune response. However, the concrete molecular mechanism remains to be discovered. Methods: We established experimental model of silicosis with wildtype and Atg5 flox/flox Dppa3 Cre/+ mice and oral administrated dioscin daily to explore the effects of dioscin on macrophages and pulmonary fibrosis. AM cell line MH-S with Atg5 silence was used to explore specific function of dioscin on macrophage-derived inflammation and the underlying molecular mechanism. Results: Dioscin could promote autophagy in macrophages. Dioscin-triggered AMs autophagy limited mitochondrial reactive oxygen species (mtROS) mass stimulated by CS, reduced mitochondria-dependent apoptosis pathway activation and facilitated cell survival. Relieved oxidative stress resulted in decreased secretion of inflammatory factors and chemokines. Dioscin treatment alleviated macrophage-derived inflammation and subsequent abnormal collagen repair. All the dioscin's protective effects were diminished in Atg5 flox/flox Dppa3 Cre/+ mice. Conclusion: Dioscin promoting autophagy leads to reduced CS-induced mitochondria-dependent apoptosis and cytokine production in AMs, which may provide concrete molecular mechanism for the therapy of silicosis.

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

“…The results from genetically modified mice showed that autophagy is vital for maintaining lung homeostasis. Increasing LC3II expression together with enhanced autophagic flux alleviates CS-induced pulmonary fibrosis by promoting autophagy in AMs [15]. However, in this study, we found that LC3II expression was decreased in the CS + Tre-treated AMs as compared with the CS-treated alone.…”

“…Autophagy, a "self-eating" catabolic process, is markedly essential for maintaining cell homeostasis and normal cellular function [56,57]. Our previous study showed activated autophagy and increased autophagosomes in AMs of silicosis patients and mouse model [13,15]. Studies reported that inhibition of autophagy in macrophages could relieve CS-induced pulmonary fibrosis [58,59].…”

“…Studies reported that inhibition of autophagy in macrophages could relieve CS-induced pulmonary fibrosis [58,59]. However, Atg5 knockdown in mice showed that impairment of autophagy aggravated CS-induced pulmonary inflammation and fibrosis [14,15]. The results from genetically modified mice showed that autophagy is vital for maintaining lung homeostasis.…”

“…AMs were collected from bronchoalveolar lavage fluid (BALF) as described previously [15]. Briefly, the BALF was centrifuged at 4 • C and 1000× g for 10 min.…”

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

“…Pulmonary brosis (PF) is a common outcome of various interstitial lung diseases, including pneumoconiosis, drug-induced brosis and idiopathic pulmonary brosis [1,2]. PF is characterized by alveolar epithelial cell injury, and the excessive proliferation of mesenchymal cells in the interstitium, which leads to the exaggerated accumulation of extracellular matrix and distorted lung architecture.…”