The Regulation Of NLRP3 Inflammasomes By Losartan And Its Role In Sepsis-induced Lung Injury

Objectives:Acute respiratory distress syndrome?ARDS?,which progresses from acute lung injury?ALI?,is one of the leading causes of death in patients with sepsis.It has been shown that the damage of pulmonary endothelial cells caused by inflammatory responses and oxidative stress is one of the major mechanisms of ALI/ARDS caused by sepsis.Several studies have shown that losartan plays a role in the inflammatory responses of various organs?such as heart,kidney,lung,etc.?by reducing inflammation,relieving tissue damage and anti-oxidation.Therefore,this study aimed to investigate whether losartan has anti-inflammatory effect and its mechanism in a mouse model of lung injury induced by LPS.Methods:We selected ICR mice in this animal experiments.After general anesthesia,the mice were administered by intraperitoneal injection?lorsartan potassium?and tracheal intubation?LPS?.After 24 hours,lung tissue samples were collected.Lung tissue hematoxylin and eosin?H&E?staining reflects the pathological changes such as inflammatory cell infiltration,edema and hemorrhage in lung tissues.Protein extracted from lung tissues was detected by enzyme colorimetric assay for the levels of myeloperoxidase?MPO?,hydrogen peroxide?H2O2?,malondialdehyde?MDA?,total antioxidant capacity?T-AOC?,catalase?CAT?and superoxide dismutase?SOD?which reflect the degree of the oxidative stress levels in lung tissues.The levels of interleukin?IL?-1?and IL-18 in lung tissues are measured by enzyme-linked immunosorbent assay?ELISA?to reflect the inflammatory responses in lung tissues.The expression of caspase-1 protein in lung tissues was detected by western blot?WB?method to reflect the activation of NLRP3 inflammasomes.Main Results:LPS treatment can lead to activation of NLRP3 inflammasomes in lung tissues and trigger uncontrolled inflammatory responses,which in turn triggers the progression of ALI/ARDS.We observed that LPS stimulated the increase of caspase-1and caspase-1 p20 in lung tissues of mice,and increased IL-1?and IL-18 levels,indicating that LPS-induced lung injury was accompanied by activation of the NLRP3inflammasomes and its downstream NLRP3/caspase-1/IL-1?pathway.In addition,LPS induced rapid oxidative stress,which showed an increase in MPO,H₂O₂,and MDA levels after 24 hours of LPS treatment,and decreased activity of T-AOC,CAT,and SOD.In contrast,losartan can attenuate LPS-induced inflammatory responses and reduce the extent of the damage of lung tissues by inhibiting the activation of NLRP3/caspase-1/IL-1?signaling pathway and the production of IL-1?and IL-18.At the same time,it inhibits LPS-induced oxidative stress.Conclusions:Losartan may ameliorate LPS-induced lung injury by inhibiting NLRP3/caspase-1/IL-1?signaling pathway and oxidative stress.Losartan or other Angiotensin Receptor Blockers?ARBs?may be an effective adjuvant pharmacologic therapy for ALI/ARDS.