Lipopolysaccharides may aggravate apoptosis through accumulation of autophagosomes in alveolar macrophages of human silicosis
Lipopolysaccharides may aggravate apoptosis through accumulation of autophagosomes in alveolar macrophages of human silicosis
复制标题
脂多糖可能通过人矽肺肺泡巨噬细胞自噬体的积累加剧细胞凋亡
DOI：
10.1080/15548627.2015.1109765
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发表时间：
2015-12-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Jie
中科院分区：
文献类型：
--
作者：
Chen, Shi;Yuan, Juxiang;Chen, Jie
矽尘主要作用于肺泡巨噬细胞（AM），并使AM凋亡增加.然而，尚不清楚自噬是否受到影响。自噬主要在应激反应中具有防御功能，有助于细胞在不利条件下的存活，相反，它也与细胞死亡有关。脂多糖（LPS）诱导巨噬细胞自噬和凋亡。LPS在矽肺患者AM自噬和凋亡中的作用尚不清楚。在这项研究中，我们收集了AM从53名男性工人接触二氧化硅，并将他们分为观察员（对照）组，和阶段I，II和III患者组。随着矽肺的发展，LC 3B、SQSTM 1/p62和BECN 1的表达水平逐渐升高，而MTOR的磷酸化水平、LAMP 2、TLR 4、MYD 88和TICAM 1的表达水平以及溶酶体的数量逐渐减少。LPS刺激触发自噬并增加AM中SQSTM 1的水平。自噬抑制剂3-甲基腺嘌呤（3 MA）可抑制矽肺患者AM中LPS诱导的凋亡。此外，3 MA逆转了LPS诱导的AM中BCL 2的降低以及BAX和CASP 3水平的升高。这些结果表明自噬体在矽肺进展过程中在AM中积累。LPS可通过TLR 4依赖的途径诱导AM形成自噬体，并可加重AM的凋亡。阻断自噬体的形成可以抑制LPS通过AM的内在凋亡途径诱导的细胞凋亡。这些发现描述了可能导致肺纤维化新的预防和治疗策略的新机制。
Silica dust mainly attacks alveolar macrophages (AMs) and increases the apoptosis of AMs in silicosis patients. However, it is still unclear whether autophagy is affected. Autophagy mainly has defensive functions in response to stress, contributing to cell survival in adverse conditions, and conversely it has also been implicated in cell death. Lipopolysaccharide (LPS) induces autophagy and apoptosis in macrophages. The role of LPS in autophagy and apoptosis in AMs of silicosis patients is unknown. In this study, we collected AMs from 53 male workers exposed to silica and divided them into an observer (control) group, and stage I, II and III patient groups. We found increased levels of LC3B, SQSTM1/p62 and BECN1，whereas the phosphorylation of MTOR，and levels of LAMP2, TLR4, MYD88, TICAM1, as well as the number of lysosomes decreased with the development of silicosis. LPS stimulation triggered autophagy and increased levels of SQSTM1 in AMs. The autophagy inhibitor, 3-methyladenine (3MA), inhibited LPS-induced apoptosis in the AMs of silicosis patients. Moreover, 3MA reversed the LPS-induced decrease in BCL2 and the increase in BAX and CASP3 levels in AMs. These results suggest that autophagosomes accumulate in AMs during silicosis progression. LPS can induce the formation of autophagosomes through a TLR4-dependent pathway, and LPS may exacerbate the apoptosis in AMs. Blockade of the formation of autophagosomes may inhibit LPS-induced apoptosis via the intrinsic apoptotic pathway in AMs. These findings describe novel mechanisms that may lead to new preventive and therapeutic strategies for pulmonary fibrosis.