Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Pharmacol Res. 2020 Aug;158:104884. doi: 10.1016/j.phrs.2020.104884. Epub 2020 May 16.
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.
特发性肺纤维化（IPF）是一种慢性且不可逆转的肺部疾病，治疗方法有限。石蒜碱（LYC）是从石蒜科植物中分离得到的一种生物碱，具有有效的抗炎、抗病毒和抗肿瘤活性。在这项研究中，我们试图确定 LYC 对博来霉素（BLM）诱导的 IPF 和 NLRP3 炎性体激活的影响。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。LYC 抑制 BLM 诱导的急性肺损伤（ALI）中小鼠活性 Caspase-1 表达和乳酸脱氢酶（LDH）释放。此外，我们的体外研究表明，LYC 抑制 LPS/ Nigericin 或 LPS/ATP 诱导的骨髓来源的巨噬细胞（BMDM）中 NACHT、LRP 和 PYD 结构域包含蛋白 3（NLRP3）炎性体激活和细胞焦亡。机制上，LYC 通过靶向 ASC 的吡喃结构域（PYD）上的 Leu9、Leu50 和 Thr53，干扰 NLRP3 与凋亡相关斑点样蛋白（ASC）的相互作用。我们的研究结果表明，LYC 通过抑制 NLRP3 炎性体激活和细胞焦亡来改善 BLM 诱导的肺纤维化，其作用靶点是 ASC 的 PYD 结构域。因此，LYC 可能是一种治疗肺部炎症和纤维化的潜在药物。
