Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis
Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis
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DOI：
10.1016/j.freeradbiomed.2021.07.009
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发表时间：
2021-07-20
影响因子：
7.4
通讯作者：
Gao, Zhenming
中科院分区：
文献类型：
--
作者：
Fan, Rong;Sui, Jidong;Gao, Zhenming
急性胰腺炎（AP）是一种与多器官功能衰竭相关的炎症性疾病。焦亡和铁亡是两种新认识的细胞死亡，焦亡和铁亡是否参与AP仍然很难确定。天然化合物Wed具有较强的抗炎和抗氧化活性，本研究旨在探讨Wed对急性胰腺炎的影响，并探讨Wed对急性胰腺炎及相关肺损伤的保护作用。我们的研究结果表明，焦凋亡抑制剂双硫仑或ferroptosis抑制剂ferrostatin-1显着减轻AP和相关的肺损伤牛磺胆酸钠或雨蛙素诱导的小鼠AP模型。通过改善病理损伤、降低血清胰腺消化酶和促炎细胞因子证明，给予Wed可改善AP和肺损伤。体内外实验结果表明，Wed广泛抑制caspase 1/caspase 11活化，降低成熟白细胞介素1（IL-1（i））和Gasdermin D N端结构域（GSDMD-N）水平。Wed处理组还沿着抑制氧化应激和脂质过氧化作用，上调铁凋亡拮抗标志物谷胱甘肽过氧化物酶4（GPX 4）。Wed促进GPX 4的转录活性和硒敏感性。此外，在雨蛙素刺激的胰腺腺泡细胞中，Wed的保护作用被GPX 4的下调显著废除。总的来说，我们的数据表明，pyroptosis和ferroptosis在AP中起着至关重要的作用。我们通过GPX 4介导的抑制焦亡和铁亡来减轻AP和相关的肺损伤。
Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure. Pyroptosis and ferroptosis are two newly recognized cell death, and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities, the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes, and proinflammatory cytokines. The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/ caspase11 activation, reduced mature interleukin-1(i (IL-1(i) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.