Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis
Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis
复制标题
Lycorine 通过抑制 NLRP3 炎性体激活和细胞焦亡改善博莱霉素诱导的肺纤维化
DOI：
10.1016/j.phrs.2020.104884
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发表时间：
2020-08-01
影响因子：
9.3
通讯作者：
Sun, Lei
中科院分区：
文献类型：
--
作者：
Liang, Qing;Cai, Wuyang;Sun, Lei
特发性肺纤维化（IPF）是一种慢性且不可逆的肺部疾病，治疗策略有限。 Lycorine (LYC) 是一种从石蒜科植物中分离出来的生物碱，具有有效的抗炎、抗病毒和抗肿瘤活性。在本研究中，我们试图确定 LYC 对博来霉素 (BLM) 诱导的 IPF 和 NLRP3 炎症小体激活的影响。我们的结果表明，LYC 治疗可改善 BLM 诱导的小鼠肺纤维化和炎症。在 BLM 诱导的小鼠急性肺损伤 (ALI) 过程中，LYC 抑制活性 Caspase-1 表达和乳酸脱氢酶 (LDH) 释放。此外，我们的体外测定表明，LYC 抑制 LPS/尼日利亚菌素或 LPS/ATP 诱导的 NACHT、LRP 和 PYD 结构域含有蛋白 3 (NLRP3) 炎性体激活以及骨髓源性巨噬细胞 (BMDM) 中的细胞焦亡。从机械角度来看，LYC 可以通过靶向 Leu9、Leu50 和 Thr53 上的热蛋白结构域 (PYD) 来干扰 NLRP3 与含有 CARD (ASC) 的凋亡相关斑点样蛋白的相互作用。我们的研究结果表明，LYC 通过靶向 ASC 的 PYD 结构域抑制 NLRP3 炎性体激活和细胞焦亡，从而改善 BLM 诱导的肺纤维化。因此，LYC可能是肺部炎症和纤维化的潜在治疗剂。
Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic strategies. Lycorine (LYC), an alkaloid isolated from Amaryllidaceae family plants, exhibits effective anti-inflammatory, antiviral, and anti-tumor activities. In this study, we attempted to determine the effect of LYC on bleomycin (BLM)-induced IPF and NLRP3 inflammasome activation. Our results demonstrated that the LYC treatment ameliorated BLM-induced pulmonary fibrosis and inflammation in mice. LYC inhibited active Caspase-1 expression and lactate dehydrogenase (LDH) release during BLM-induced acute lung injury (ALI) in mice. Furthermore, our in vitro assay showed that LYC inhibited LPS/Nigericin- or LPS/ATP-induced NACHT, LRP and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pyroptosis in bone marrow-derived macrophages (BMDMs). Mechanically, LYC could disturb the interaction of NLRP3 with apoptosis-associated speck-like protein containing a CARD (ASC) by targeting the pyrin domain (PYD) on Leu9, Leu50, and Thr53. Our findings indicate that LYC ameliorated BLM-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and pyroptosis through targeting the PYD domain of ASC. Thus, LYC might be a potential therapeutic agent for pulmonary inflammation and fibrosis.