Curine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Downregulating the TLR4/MD-2/NF-κB(p65) Signaling Pathway

Acute lung injury is characterized by alveolar-capillary barrier rupture, neutrophil-mediated airway inflammation, and tissue hypoxia. Since no effective pharmacotherapy is currently available, alternatives to improve its condition are mandatory. Recent studies demonstrated that curine, a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum (A.St.-Hil.) Miers, Menispermaceae, with anti-allergic and anti-inflammatory properties, inhibited lipopolysaccharide-mediated acute pulmonary response in mice. Therefore, this study aimed to investigate curine's mechanism of action in a lipopolysaccharide-induced acute lung injury model. Curine inhibited the recruitment of inflammatory cells to the bronchoalveolar lavage fluid, mainly dependent on neutrophil migration, and restored the pulmonary architecture by reducing edema, vascular permeability, and the total protein content as well as the wet/dry ratio of the lung. Curine also decreased the INF-alpha, IL-1 beta, and IL-6 production through downregulating the toll-like receptor 4 receptor expression and the nuclear factor-kappa B (p65) phosphorylation. In silico analysis demonstrated that curine made hydrophobic interactions with the Leu78, Ile80, Phe121, Ile 124, Phe126, and Ile 152 amino acids of the hydrophobic cavity of the MD-2 receptor. This curine interaction presented stability during the simulation, remaining linked to the active site, indicating an antagonistic interaction with the molecular complex lipopolysaccharides/toll-likereceptor/4 myeloid differentiation factor 2.