title: CCAAT/enhancer-binding protein δ is a critical mediator of lipopolysaccharide-induced acute lung injury.
abstract: Although inflammation plays a central role in the pathogenesis of acute lung injury, the molecular mechanisms underlying inflammatory responses in acute lung injury are poorly understood, and therapeutic options remain limited. CCAAT/enhancer-binding proteins, C/EBPβ and C/EBPδ, are expressed in the lung and have been implicated in the regulation of inflammatory mediators. However, their functions in lung pathobiological characteristics are not well characterized. Herein, we show that C/EBPβ and C/EBPδ are activated in mouse lung after intrapulmonary deposition of lipopolysaccharide (LPS). Mice carrying a targeted deletion of the C/EBPδ gene displayed significant attenuation of the lung permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), and neutrophils in bronchial alveolar lavage fluids compared with wild-type mice. These phenotypes were consistent with morphological evaluation of lung, which showed reduced inflammatory cell influx and minimal intra-alveolar hemorrhage. Moreover, mutant mice expressed considerably less tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 in bronchial alveolar lavage fluids in LPS-injured lung compared with wild-type mice. In contrast, C/EBPβ deficiency had no effect on LPS-induced lung injury. By using small-interfering RNA-mediated knockdown for C/EBPδ, we demonstrate, for the first time to our knowledge, that C/EBPδ plays a critical role for the tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 production in LPS-stimulated alveolar macrophages. These findings demonstrate that C/EBPδ, but not C/EBPβ, plays an important role in LPS-induced lung inflammatory responses and injury.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, the Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Yan
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.forename: Huifang
authors.initials: H
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000172:deficiency / Q000378:metabolism*; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000473:pathology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497253:Cebpd protein, mouse; D018925:Chemokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D051743:CCAAT-Enhancer-Binding Protein-delta; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases