CCAAT/Enhancer-Binding Protein δ Is a Critical Mediator of Lipopolysaccharide-Induced Acute Lung Injury

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/EBP beta and C/EBP delta, 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/EBP beta and C/EBP delta are activated in mouse Lung after intrapulmonary deposition of lipopolysaccharide (LPS). Mice carrying a targeted deletion of the C/EBP delta 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-alpha, IL-6, and macrophage inflammatory protein-2 in bronchial alveolar lavage fluids in LPS-injured Lung compared with wild-type mice. In contrast, C/EBP beta deficiency had no effect on LPS-induced lung injury. By using small-interfering RNA-mediated knockdown for C/EBP delta, we demonstrate, for the first time to our knowledge, that C/EBP delta plays a critical role for the tumor necrosis factor-alpha, IL-6, and macrophage inflammatory protein-2 production in LPS-stimulated alveolar macrophages. These findings demonstrate that C/EBP delta, but not C/EBP beta, plays an important role in LPS-induced lung inflammatory responses and injury. (Am J Pathol 2013, 182: 420-430; http://dx.doi.org/10.1016/j.ajpath.2012.10.013)