{"title":"在酒精诱导的小鼠ACLF模型中,Gasdermin D缺失可预防肝损伤并加重肝外损伤。","authors":"Martí Ortega-Ribera, Yuan Zhuang, Veronika Brezani, Radhika S Joshi, Zsuzsanna Zsengeller, Prashanth Thevkar Nagesh, Aditi Datta, Gyongyi Szabo","doi":"10.1136/egastro-2024-100151","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear.</p><p><strong>Methods: </strong>ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5 g/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis.</p><p><strong>Results: </strong>Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes.</p><p><strong>Conclusion: </strong>Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100151"},"PeriodicalIF":0.0000,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934631/pdf/","citationCount":"0","resultStr":"{\"title\":\"Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF.\",\"authors\":\"Martí Ortega-Ribera, Yuan Zhuang, Veronika Brezani, Radhika S Joshi, Zsuzsanna Zsengeller, Prashanth Thevkar Nagesh, Aditi Datta, Gyongyi Szabo\",\"doi\":\"10.1136/egastro-2024-100151\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear.</p><p><strong>Methods: </strong>ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5 g/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis.</p><p><strong>Results: </strong>Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes.</p><p><strong>Conclusion: </strong>Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.</p>\",\"PeriodicalId\":72879,\"journal\":{\"name\":\"eGastroenterology\",\"volume\":\"3 1\",\"pages\":\"e100151\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-03-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934631/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"eGastroenterology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1136/egastro-2024-100151\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"eGastroenterology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1136/egastro-2024-100151","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF.
Background: Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear.
Methods: ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5 g/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis.
Results: Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes.
Conclusion: Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.