Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China.
Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan, China.
Mediators Inflamm. 2021 Feb 19;2021:8086253. doi: 10.1155/2021/8086253. eCollection 2021.
Patients being treated for pulmonary tuberculosis often suffer liver injury due to the effects of anti-TB drugs, and the underlying mechanisms for those injuries need to be clarified. In this study, rats and hepatic cells were administrated isoniazid (INH) and rifampin (RIF) and then treated with NLRP3-inflammasome inhibitors (INF39 and CP-456773) or NLRP3 siRNA. Histopathological changes that occurred in liver tissue were examined by H&E staining. Additionally, the levels IL-33, IL-18, IL-1, NLRP3, ASC, and cleaved-caspase 1 expression in the liver tissues were also determined. NAT2 and CYP2E1 expression were identified by QRT-PCR analysis. Finally, assays were performed to examine the effects of siRNA targeting NLRP3. Treatment with the antituberculosis drugs caused significant liver injuries, induced inflammatory responses and oxidative stress (OS), activated NLRP3 inflammasomes, reduced the activity of drug-metabolizing enzymes, and altered the antioxidant defense system in rats and hepatic cells. The NLRP3 inflammasome was required for INH- and RIF-induced liver injuries that were produced by inflammatory responses, OS, the antioxidant defense system, and drug-metabolizing enzymes. This study indicated that the NLRP3 inflammasome is involved in antituberculosis drug-induced liver injuries (ATLIs) and suggests NLRP3 as a potential target for attenuating the inflammation response in ATLIs.
治疗肺结核的患者常因抗结核药物的作用而遭受肝损伤，需要阐明这些损伤的潜在机制。在这项研究中，给大鼠和肝细胞用异烟肼（INH）和利福平（RIF）处理，然后用 NLRP3 炎性体抑制剂（INF39 和 CP-456773）或 NLRP3 siRNA 处理。通过 H&E 染色检查肝组织中发生的组织病理学变化。此外，还测定了肝组织中 IL-33、IL-18、IL-1、NLRP3、ASC 和切割型半胱天冬酶 1 的表达水平。通过 QRT-PCR 分析鉴定 NAT2 和 CYP2E1 的表达。最后，进行了针对 NLRP3 的 siRNA 的作用检测实验。抗结核药物治疗导致大鼠和肝细胞发生显著的肝损伤，引发炎症反应和氧化应激（OS），激活 NLRP3 炎性体，降低药物代谢酶的活性，并改变抗氧化防御系统。NLRP3 炎性体是 INH 和 RIF 诱导的肝损伤所必需的，其由炎症反应、OS、抗氧化防御系统和药物代谢酶产生。这项研究表明，NLRP3 炎性体参与抗结核药物引起的肝损伤（ATLIs），并提示 NLRP3 可能是减轻 ATLIs 炎症反应的潜在靶点。
