Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI)...Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI).This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.Methods:Cases of PA-ILI,non-PA-ILI,and control subjects were collected from patients hospitalized at Zhongshan Hospital,Fudan University(Shanghai,China)between 2012 and 2019.A mouse model of PA-ILI was established using monocrotaline administration.Liver RNA sequencing was performed,and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database.Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13(ADAMTS13)were applied.The necrotic liver area,hepatic platelet accumulation,and von Willebrand factor(VWF)deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.Results:Hepatic platelet accumulation,necrotic area expansion,and increased VWF expression were observed in both PA-ILI patients and mice.The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice.Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice.Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation,downregulated VWF expression,and mitigated mouse hepatic necrosis.Conclusions:Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice.Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI,suggesting that ADAMTS13 could be a potential therapeutic target for this condition.展开更多
基金funded by the Shanghai Science and Technology Commission(21Y11921800)Zhongshan Hospital,Fudan University(2019ZSGG12 and 2020ZSLC24).
文摘Background and Aims:Pyrrolizidine alkaloids(PAs),widely distributed in plants,are known to induce liver failure.Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury(PA-ILI).This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.Methods:Cases of PA-ILI,non-PA-ILI,and control subjects were collected from patients hospitalized at Zhongshan Hospital,Fudan University(Shanghai,China)between 2012 and 2019.A mouse model of PA-ILI was established using monocrotaline administration.Liver RNA sequencing was performed,and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database.Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13(ADAMTS13)were applied.The necrotic liver area,hepatic platelet accumulation,and von Willebrand factor(VWF)deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.Results:Hepatic platelet accumulation,necrotic area expansion,and increased VWF expression were observed in both PA-ILI patients and mice.The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice.Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice.Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation,downregulated VWF expression,and mitigated mouse hepatic necrosis.Conclusions:Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice.Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI,suggesting that ADAMTS13 could be a potential therapeutic target for this condition.
