CCAAT/enhancer-binding protein δ is a critical mediator of lipopolysaccharide-induced acute lung injury

Am J Pathol. 2013 Feb;182(2):420-30. doi: 10.1016/j.ajpath.2012.10.013. Epub 2012 Nov 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / enzymology
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology*
  • Animals
  • Bronchoalveolar Lavage Fluid
  • CCAAT-Enhancer-Binding Protein-delta / deficiency
  • CCAAT-Enhancer-Binding Protein-delta / metabolism*
  • Cell Line
  • Chemokines / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Knockdown Techniques
  • Interleukin-6 / metabolism
  • Lipopolysaccharides
  • Luciferases / metabolism
  • Lung / enzymology
  • Lung / pathology
  • Macrophages, Alveolar / enzymology
  • Macrophages, Alveolar / pathology
  • Mice
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cebpd protein, mouse
  • Chemokines
  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • CCAAT-Enhancer-Binding Protein-delta
  • Luciferases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases