硫化氢对脓毒症肠黏膜损伤的保护机制研究

Study on protective mechanism of hydrogen sulfide in intestinal mucosal injury in sepsis

脓毒症是一种临床常见的急危重疾病,因其极高的发病率及致死性被广泛关注.肠道作为脓毒症损伤的靶器官,其细胞紧密连接等物理屏障及抗原呈递细胞相关免疫屏障的破坏促进了多器官损伤的发生.自噬作为生物进化中保守的细胞代谢过程,通过清除细胞内坏死的细胞器、异常蛋白质聚集体及微生物等调控组织器官的稳态和细胞更新.因此,自噬在维持肠道稳态中起关键作用.有研究表明,自噬功能障碍与脓毒症肠损伤密切相关,但其作用的特异性机制仍不清楚.硫化氢作为一种新型气体信号传递分子,有大量研究证明其可以通过腺苷酸活化蛋白激酶/哺乳动物雷帕霉素靶蛋白(AMPK/mTOR)、丝裂素活化蛋白激酶/硫氧还蛋白结合蛋白(MAPK/TXNIP)、转录因子E2相关因子2(Nrf 2)-活性氧(ROS)-AMPK等通路上调或下调自噬对脓毒症组织器官发挥保护作用.尽管如此,脓毒症仍无特异性的治疗方案,这可能与我们目前的研究尚未发现器官损伤的特异性通路信号有关.为此,我们探讨了硫化氢通过AMPK/沉默信息调节因子1(SIRT1)途径调控自噬缓解脓毒症相关性肠损伤的可能性,以期为脓毒症的精准治疗及药物研究提供思路.

Sepsis is a common clinical emergency and critical illness,which has attracted wide attention due to its extremely high morbidity and lethality.The intestine is the target organ of sepsis injury.The destruction of physical barriers such as tight cell junctions and immune barriers related to antigen-presenting cells promotes the occurrence of multiple organ injuries.Autophagy,as a conservative cell metabolism process in biological evolution,regulates the homeostasis and cell renewal of organs and tissues by removing necrotic organelles,abnormal protein aggregates,and microorganisms,etc.in cells.Therefore,autophagy plays a key role in maintaining intestinal lumen homeostasis.Studies have shown that autophagy dysfunction is closely related to septic intestinal injury,but the specific mechanism of its action is still unclear.As a new type of gas signal transmission molecule,a large number of studies have proved that hydrogen sulfide can up-regulate or down-regulate autophagy through AMP-activated protein kinase/mammalian target of rapamycin(AMPK/mTOR),mitogen-activation protein kinase/thioredoxin interacting protein(MAPK/TXNIP),nuclear factor-erythroid 2-related factor 2-reactive oxygen species-AMPK(Nrf2-ROS-AMPK)and other pathways to play a role to protect tissues and organs in sepsis.Despite this situation,there is still no specific plan for treatment of sepsis,which may be related to the fact that our current research has not found specific pathway signals for organ damage.For this reason,we explored the regulation of autophagy by hydrogen sulfide through AMPK/silence information regulator 1(SIRT1)pathway that may get the possibility of alleviating the sepsis-related intestinal injury,which will help provide ideas for the precise treatment and drug research of sepsis.