Direct factor Xa inhibition attenuates acute lung injury progression via modulation of the PAR-2/NF-κB signaling pathway.

The role of coagulation in acute lung injury (ALI) remains unclear. As factor Xa-dependent protease-activated receptor 2 (PAR-2) is reported to be an important target in blood coagulation and other processes, an inhibitor of factor Xa, rivaroxaban, was tested in vivo in C57BL/6 mice with ALI induced by intratracheal injections of lipopolysaccharide (LPS) and in vitro in LPS-stimulated human umbilical vein endothelial cells. Plasma concentrations and coagulation indices were measured in mice fed normal chow or chow containing rivaroxaban (0.2 or 0.4 mg/g) for 10 days. The rivaroxaban-treated mice had significantly reduced neutrophil sequestration with preservation of the lung tissue architecture compared with that in the untreated controls. The levels of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6, as well as total protein and Evans blue concentrations, were all significantly reduced in bronchoalveolar lavage fluid from mice treated with rivaroxaban. Rivaroxaban treatment also ameliorated the LPS-induced PAR-2 increase and nuclear factor kappa B (NF-κB) activation. In vitro, cells treated with rivaroxaban had higher cell viability with an attenuation of LPS-induced increases in membrane permeability and proinflammatory cytokine levels, as well as reduced apoptosis. Furthermore, rivaroxaban inhibited the phosphorylation of TAK1 and p65. These data show that rivaroxaban attenuates ALI and inflammation by inhibiting the PAR-2/NF-κB signaling pathway.