Anti-inflammatory Effect of Nestorone in a Lipopolysaccharide-induced Acute Lung Injury Model through Regulation of the TLR-4/Myd88/NF-κB Signaling Pathway

Progesterone plays a crucial and indispensable role in regulating immunity and attenuating inflammation. Nestorone ^® (NES, segesterone acetate) is a steroidal progestin and a 19-norprogesterone derivative with no -CH3 group radical at the 6-position. Here, we showed that NES enhanced the viability of lipopolysaccharide (LPS)-stimulated THP-1 cell-derived macrophages, potently inhibiting both arms of the Toll-like receptor 4 (TLR-4) signaling cascade triggered by LPS, especially the TLR-4/MyD88/NF-κB pathway. In addition, NES exerted an anti-inflammatory effect by significantly decreasing the secretion of inflammatory cytokines and chemokines in type II alveolar epithelial A549 cells and THP-1 cell-derived macrophages stimulated by LPS. Furthermore, we evaluated the potential of pre-treatment with NES 2 hours before LPS treatment to rescue the lung from acute LPS-induced injury, using an LPS-induced acute lung injury (ALI) mouse model. In this study NES alleviated lung inflammation and damage through reducing leukocyte infiltration and inflammatory cytokines in mouse bronchoalveolar lavage fluid (BALF) and lung tissues. Interestingly, we found that NES at 1 mg/kg was superior to 0.1 or 10 mg/kg or to dexamethasone (DEX, 5 mg/kg) in prolonging survival in mice experiencing lethal LPS-induced injury, decreasing acute lung inflammation, and alleviating diffuse alveolar damage in the lungs of C57 mice. Overall, our study suggested that concentration was one of the key factors in determining the anti-inflammatory potency of NES, and therefore NES may serve as a promising novel therapeutic agent to treat pulmonary inflammatory diseases such as ALI/acute respiratory distress syndrome (ARDS) by modulating TLR-4 signaling.