FXR Protects Lung from Lipopolysaccharide-Induced Acute Injury

Abstract

Acute lung injury and its more severe form, acute respiratory distress syndrome, are characterized by an acute inflammatory response in the airspaces and lung parenchyma. The nuclear receptor farnesoid X receptor (FXR) is expressed in pulmonary artery endothelial cells. Here, we report a protective role of FXR in a lipopolysaccharide-induced mouse model of acute lung injury. Upon intratracheal injection of lipopolysaccharide, FXR-/- mice showed higher lung endothelial permeability, released more bronchoalveolar lavage cells to the alveoli, and developed acute pneumonia. Cell adhesion molecules were expressed at higher levels in FXR-/- mice as compared with control mice. Furthermore, lung regeneration was much slower in FXR-/- mice. In vitro experiments showed that FXR activation blocked TNFα-induced expression of P-selectin but stimulated proliferation of lung microvascular endothelial cells through up-regulation of Foxm1b. In addition, expression of a constitutively active FXR repressed the expression of proinflammatory genes and improved lung permeability and lung regeneration in FXR-/- mice. This study demonstrates a critical role of FXR in suppressing the inflammatory response in lung and promoting lung repair after injury.