title: 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.
authors.affiliation: Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Donna
authors.initials: D
authors.lastname: Yu
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000096:biosynthesis; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015815:Cell Adhesion Molecules; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008070:Lipopolysaccharides; D019007:P-Selectin; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated; C491524:Foxm1 protein, mouse