Effect And Mechanism Of NLRP3 Inflammasome Targeted Therapy On Septic Lung Injury

Background: Sepsis(sepsis)is a life-threatening multi-organ dysfunction caused by infection and a disordered immune response,which is characterized by high morbidity,high mortality and short survival time.Lung is the most among sepsis,and the current lack of effective treatment plan for sepsis lung injury makes the morbidity and mortality of sepsis lung injury high,bringing huge medical economic burden to the society.Therefore,it is urgent and necessary to explore the more accurate and effective treatment method of sepsis lung injury.Recently,NLRP3 inflammasomes were found to play a pivotal role in the development and development of septic lung injury,It is expected to be a new therapeutic target for septic lung injury.However,there are no pathway drugs targeting NLRP3 inflammasome in clinical use,so it is urgent and necessary to explore the inhibitors of NLRP3 inflammasome for clinical transformation.Based on this,we screened the compound library and found that an indexing derivative 4-[2-(1-H-index-3-yl)-1,3-thiazol-4-yl] benzene-1,2-diol(1,2-diol)had obvious inhibitory effect on the activation of NLRP3 inflammasome.This topic aims to clarify 1,2-diol to septic lung injury at the same time,we can further explore its mechanism.Methods:1.Small molecule compound 1,2-diol that efficiently inhibited the NLRP3 inflammasome was obtained by using a compound library screening.Mouse peritoneal macrophages were extracted for in vitro experiments,and the molecular biological means of ELISA,immunoprecipitation and immunofluorescence clarified the specific mechanism.2.In vivo animal models used intraperitoneal injection of LPS and LPS administered via tracheal lungs to septic lung injury model,and compared the lung pathological injury in the experimental group of mice administered 1,2-diol and control mice.The concentration changes of cytokines IL-1β and TNF-α in blood and alveolar lavage fluid further clarified the in vivo effect of small molecule inhibitors in a mouse model of septic lung injury.Results:1.Small molecule compound 1,2-diol can effectively inhibit the activation of NLRP3 inflammasome in peritoneal macrophages;2.1,2-diol can reduce lung damage and the concentration of inflammatory factor IL-1β in blood and alveolar lavage fluid;3.Small molecule compound 1,2-diol can selectively inhibit the release of cytokine IL-1β without affecting the release of broad spectrum inflammatory factor TNF-α;4.1,2-diol has no significant inhibitory effect on K+ efflux upstream of NLRP3inflammasome;1,2-diol suppresses the inflammasome by acting on intermolecular interactions.Conclusion:1,2-diol can inhibit pyroptosis and inflammatory cytokine release by blocking the activation of NLRP3 inflammasome,and by acting on molecular interactions,which has obvious protective therapeutic effect in mice with septic lung injury.