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: Chunguang Yan, Peter F Johnson, Huifang Tang, Yan Ye, Min Wu, Hongwei Gao
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 2 Pg. 420-30 (Feb 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23177475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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