Acetaldehyde dehydrogenase 2(ALDH2)mutations are commonly found in a subgroup of the Asian population.However,the role of ALDH2 in septic acute respiratory distress syndrome(ARDS)remains unknown.Here,we showed that hu...Acetaldehyde dehydrogenase 2(ALDH2)mutations are commonly found in a subgroup of the Asian population.However,the role of ALDH2 in septic acute respiratory distress syndrome(ARDS)remains unknown.Here,we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS.Intriguingly,ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA(cfDNA)and myeloperoxidase(MPO)-DNA than ALDH2WT-ARDS patients.To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS,we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice.In clinically relevant mouse sepsis models,Aldh2-/-mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis,a specific process that releases neutrophil extracellular traps(NETs)from neutrophils.Furthermore,we discovered that NETosis strongly promoted endothelial destruction,accelerated vascular leakage,and exacerbated septic ARDS.At the molecular level,ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4(PAD4)to inhibit NETosis,which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP.Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis.Together,our data reveal a novel ALDH2-based protective mechanism against septic ARDS,and the activation of ALDH2 may be an effective treatment strategy for sepsis.展开更多
Background:Pulmonary embolism(PE)is the third most common cause of cardiovascular-related deaths globally;however,the causal relationship between gut microbiota and PE remains unclear.This study aimed to explore the i...Background:Pulmonary embolism(PE)is the third most common cause of cardiovascular-related deaths globally;however,the causal relationship between gut microbiota and PE remains unclear.This study aimed to explore the impact of gut microbiota on PE.Methods:This study utilized a 2-sample Mendelian randomization(MR)design to analyze gut microbiota genome-wide association study data from the MiBioGen database and PE data from the FinnGen database.Statistical methods,such as inverse variance-weighted,MR-Egger,weighted median,and weighted modes,were used to investigate the causal relationship between the gut microbiota and PE.Moreover,a sensitivity analysis was conducted to assess the robustness of the results.Results:MR analysis revealed that gut microbiota genera Intestinimonas(odds ratio[OR]:0.797;95%confidence interval[CI]:0.666–0.952;P=0.013)and Roseburia(OR:0.752;95%CI:0.575–0.984;P=0.038)have a protective effect on PE.Conversely,an increased abundance of the phylum Lentisphaerae(OR:1.217;95%CI:1.033–1.434;P=0.019),class Lentisphaeria(OR:1.219;95%CI:1.010–1.471;P=0.039),order Gastranaerophilales(OR:1.209;95%CI:1.017–1.437;P=0.031),order Victivallales(OR:1.219;95%CI:1.010–1.471;P=0.039),and the genus Ruminococcus gauvreauii(OR:1.274;95%CI:1.015–1.599;P=0.037)increases the risk of developing PE.Sensitivity analysis indicated no heterogeneity or horizontal pleiotropy.Conclusion:Seven gut microbiotas,including the phylum Lentisphaerae,class Lentisphaeria,orders Gastranaerophilales and Victivallales,and genera R.gauvreauii,Intestinimonas,and Roseburia,were causally associated with PE.These findings may contribute significantly to the prevention of PE through dietary modifications and microbiome interventions.展开更多
基金supported by the State Key Program of the National Natural Science Foundation of China(82030059)the National Science Fund for Distinguished Young Scholars(82325031)+7 种基金the National Natural Science Regional Innovation Fund Joint Fund Key Support Projects(U23A20485)the National Natural Science Foundation of China(82072144,82172127)the National Key R&D Program of China(2020YFC1512700,2020YFC1512705,2020YFC1512703)the Key R&D Program of Shandong Province(2021ZLGX02,2021SFGC0503,2022ZLGX03)the Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)the Taishan Young Scholar Program of Shandong Province(tsqn202211312)the Clinical Research Project of Shandong University(2021SDUCRCC006)the Interdisciplinary Young Researcher Groups Program of Shandong University(2020QNQT004).
文摘Acetaldehyde dehydrogenase 2(ALDH2)mutations are commonly found in a subgroup of the Asian population.However,the role of ALDH2 in septic acute respiratory distress syndrome(ARDS)remains unknown.Here,we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS.Intriguingly,ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA(cfDNA)and myeloperoxidase(MPO)-DNA than ALDH2WT-ARDS patients.To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS,we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice.In clinically relevant mouse sepsis models,Aldh2-/-mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis,a specific process that releases neutrophil extracellular traps(NETs)from neutrophils.Furthermore,we discovered that NETosis strongly promoted endothelial destruction,accelerated vascular leakage,and exacerbated septic ARDS.At the molecular level,ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4(PAD4)to inhibit NETosis,which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP.Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis.Together,our data reveal a novel ALDH2-based protective mechanism against septic ARDS,and the activation of ALDH2 may be an effective treatment strategy for sepsis.
基金supported by National Natural Science Foundation of China(82302433)Natural Science Foundation of Shandong Province(ZR2023QH324,ZR2022QH018)+1 种基金Taishan Young Scholar Program of Shandong Province(tsqn202306353)China International Medical Foundation(Z-2017-24-2421)。
文摘Background:Pulmonary embolism(PE)is the third most common cause of cardiovascular-related deaths globally;however,the causal relationship between gut microbiota and PE remains unclear.This study aimed to explore the impact of gut microbiota on PE.Methods:This study utilized a 2-sample Mendelian randomization(MR)design to analyze gut microbiota genome-wide association study data from the MiBioGen database and PE data from the FinnGen database.Statistical methods,such as inverse variance-weighted,MR-Egger,weighted median,and weighted modes,were used to investigate the causal relationship between the gut microbiota and PE.Moreover,a sensitivity analysis was conducted to assess the robustness of the results.Results:MR analysis revealed that gut microbiota genera Intestinimonas(odds ratio[OR]:0.797;95%confidence interval[CI]:0.666–0.952;P=0.013)and Roseburia(OR:0.752;95%CI:0.575–0.984;P=0.038)have a protective effect on PE.Conversely,an increased abundance of the phylum Lentisphaerae(OR:1.217;95%CI:1.033–1.434;P=0.019),class Lentisphaeria(OR:1.219;95%CI:1.010–1.471;P=0.039),order Gastranaerophilales(OR:1.209;95%CI:1.017–1.437;P=0.031),order Victivallales(OR:1.219;95%CI:1.010–1.471;P=0.039),and the genus Ruminococcus gauvreauii(OR:1.274;95%CI:1.015–1.599;P=0.037)increases the risk of developing PE.Sensitivity analysis indicated no heterogeneity or horizontal pleiotropy.Conclusion:Seven gut microbiotas,including the phylum Lentisphaerae,class Lentisphaeria,orders Gastranaerophilales and Victivallales,and genera R.gauvreauii,Intestinimonas,and Roseburia,were causally associated with PE.These findings may contribute significantly to the prevention of PE through dietary modifications and microbiome interventions.
