Adenoviral Gene Transfer Of SOCS-1 Ameliorates Smoke Inhalation Induced Acute Lung Injury

Acute lung injury/acute respiratory distress syndrome(ALI/ARDS)is a devastating clinical problem associated with high mortality.The pathogenesis of ALI is related to the apoptosis of lung epithelial cells and inflammation.Suppressor of cytokine signaling-1(SOCS-1)is known to exert its protective effects against apoptosis and is a negative regulator of proinflammatory cytokine signaling.We therefore hypothesized that SOCS-1 may be a crucial cytoprotective regulator and key mediator against apoptosis and inflammatory responses in acute lung injury induced by smoke inhalation.To test this hypothesis,we first determined whether SOCS-1 can improve smoke inhalation-induced lung injury in mice by transfection with over-expressed SOCS-1.We found that overexpression of SOCS-1 significantly increased the survival of mice and improved smoke inhalation-induced ALI.We also investigated the effect of SOCS-1 expression on smoke-induced apoptosis of small airway epithelial cells(SAEC)in vitro.It was found that overexpression of SOCS-1 in SAEC inhibits smoke-induced apoptosis,and its mechanisms include inhibiting ASK-1 expression by inducing its ubiquitination and inhibiting the formation of smoke-induced DISC.Afterwards,we studied the inflammatory mechanism of smoke-induced ALI in smoke-treated alveolar macrophages and found that smoke-induced ATP outflow stimulated the P2X7 receptor and induced K~+efflux,thereby promoting the formation of NALP3 and activation of caspase-1.In addition,we investigated the effect of SOCS-1 on inflammation in smoke-induced ALI by extracting alveolar macrophages from Ad-GFP or Ad-SOCS-1 mice.Our study showed that SOCS-1 can reduce the ATP and K~+outflow caused by smoke,inhibit the smoke-induced assembly of the inflammasome,and reduce the activation of caspase-1 and IL-1?,thereby inhibiting the smoke-induced inflammatory response.Our research indicated that in Ad-SOCS-1 animals,inflammasome assembly and the activations of caspase-1 and IL-1?were reduced remarkably.