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  • Title: Binding domain peptide ameliorates alveolar hypercoagulation and fibrinolytic inhibition in mice with lipopolysaccharide-induced acute respiratory distress syndrome Via NF-κB signaling pathway.
    Author: Wang Y, Wu Y, Liu B, Yang H, Qian H, Cheng Y, Li X, Yang G, Zheng X, Shen F.
    Journal: Am J Transl Res; 2022; 14(6):3854-3863. PubMed ID: 35836863.
    Abstract:
    BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are shown to be associated with refractory hypoxemia in acute respiratory distress syndrome (ARDS), and the NF-κB pathway is involved in this process. The purpose of this study is to explore the role of NEMO-binding domain peptide (NBDP) in alleviating alveolar hypercoagulation and fibrinolytic inhibition induced by lipopolysaccharide (LPS) in ARDS mice and its related mechanisms. MATERIALS AND METHODS: ARDS was induced by inhalation of LPS (mg/L) in adult male BALB/c mice. Mice were treated with intratracheal inhalation of NBDP or saline aerosol at increased concentrations 30 minutes before LPS administration. Six hours after LPS treatment, bronchoalveolar lavage fluids (BALF) were collected and then all mice were euthanized. In addition, coagulation and fibrinolysis associated factors in lung tissues and BALF were detected, and the activation of NF-κB signaling pathway was observed. RESULTS: NBDP pretreatment dose-dependently inhibited the expression of tissue factor (TF) and plasminogen activator inhibitor (PAI) 1 in lung tissues, reduced the secretions of TF, PAI-1, thrombin-antithrombin (TAT) complex, and promoted activated protein C (APC) secretion in BALF induced by LPS. LPS-induced high expression of pulmonary procollagen peptide type lll (PIIIP) was also reduced in a dose-dependent manner under NBDP pretreatment. Western blotting showed that NBDP pretreatment significantly attenuated LPS-induced activation of IKKα/β, Iκα and NF-κB p65. NBDP pretreatment also inhibited the DNA binding activity of p65 induced by LPS. We also noticed that NBDP protected mice against LPS-induced lung injury in a dose-dependent manner. CONCLUSIONS: The experimental findings demonstrate that through inhibiting the NF-κB signaling pathway, NBDP dose-dependently ameliorates LPS-induced alveolar hypercoagulation and fibrinolytic inhibition, which is expected to be a new therapeutic target to correct the abnormalities of alveolar coagulation and fibrinolytic pathways in ARDS.
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