Research Of Protective Effect Of γ-Secretase Inhibitor DAPT In Zymosan-induced Acute Lung Injury And Systemic Inflammation

Multiple organ dysfunction syndrome (MODS) caused by sepsis is theleading cause of morbidity and mortality in current ICU practice, and lung is themost common primary organ of injury, manifested by pulmonary dysfunction andpresents before any evidence of other organ dysfunction, while the underlyingmechanisms remain incompletely understood. Notch signal pathway, one of themost significant pathways in cell fate determination, has been demonstratedintimate association with immune/inflammatory reaction. We hypothesized thatnotch signal pathway is involved in the emergence and development of MODS.Results showed that lung notch intracellular domain (NICD) expression wasincreased6h after zymosan (ZY) injection and achieved to its peak at24h afterzymosan administration, and both pretreatment and posttreatment with γ-secretase inhibitor DAPT reduced lung injury by attenuating lung histopathology,lung permeability (protein concentration in BALF, and lung W/D weight ratio), as well as lung inflammation (BALF cell count, lung MPO and TNF-α), alleviatedsystemic inflammation and tissue damage, and thus improved the7-day survivalrate in zymosan-challenged mice. We conclude that both pretreatment andposttreatment with γ-secretase inhibitor DAPT protect against generalizedinflammation and its associated acute lung injury by blockade of activation ofnotch signal in zymosan-challenged mice, which may provide a new target to thetherapy of critically ill patients.