ABSTRACT: BACKGROUND:It has been confirmed that NF-?B p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-?B cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in ARDS remains to be elucidated. PURPOSE:We explored the efficacy and potential mechanism of SN50 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS in mice. MATERIALS AND METHODS:Mouse ARDS was made by 50??l of lipopolysaccharide (LPS) (4?mg/ml) inhalation. Male BALB/c mice were intraperitoneally injected with different does of SN50 1?h before LPS inhalation. Lung tissues were collected for hematoxylin-eosin (HE) staining, wet/dry ratio. Pulmonary expressions of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), collagen III, as well as phosphorylated p65 (p-p65), p65 in nucleus (p'-p65), I?B? and IKK?/? were measured. Bronchoalveolar lavage fluid (BALF) was gathered to test the concentrations of TF, PAI-1, activated protein C (APC) and thrombinantithrombin complex (TAT). DNA binding activity of NF-?B p65 was also determined. RESULTS:After LPS stimulation, pulmonary edema and exudation and alveolar collapse occured. LPS also stimulated higher expressions of TF and PAI-1 in lung tissues, and higher secretions of TF, PAI-1, TAT and low level of APC in BALF. Pulmonary collagen III expression was obviously enhanced after LPS inhalation. At same time, NF-?B signaling pathway was activated with LPS injury, shown by higher expressions of p-p65, p'-p65, p-IKK?/?, p-I?? in pulmonary tissue and higher level p65 DNA binding activity. SN50 dose-dependently inhibited TF, PAI-1 and collagen IIIexpressions, and decreased TF, PAI-1, TAT but increased APC in BALF. SN50 treatment attenuated pulmonary edema, exudation and reduced lung tissue damage as well. SN50 application significantly reduced p'-p65 expression and weakened p65 DNA binding activity, but expressions of p-p65, p-IKK?/?, p-I?? in cytoplasm of pulmonary tissue were not affected. CONCLUSIONS:SN 50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in ARDS via inhibition of NF-?B p65 translocation. Our data demonstrates that NF-?B p65 pathway is a viable new therapeutic target for ARDS treatment.
