RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease and lung cancer. The mechanisms by which smoking induces pulmonary dysfunction are complex, involving stress from toxic components and inflammatory responses. Although CCCAAT/enhancer-binding protein (C/EBP)-β is known as a key intracellular regulator of inflammatory signaling, its role in pulmonary inflammation has not been established. OBJECTIVES: To characterize the role of C/EBPβ in the airway epithelial response to cigarette smoke. METHODS: mRNA expression in the airway epithelium of current, former, and never-smokers, and in in vitro cigarette smoke extract-treated primary human airway epithelial cells, was analyzed by microarray and quantitative real-time polymerase chain reaction, respectively. Mice with lung epithelial-specific inactivation of C/EBPβ were generated and exposed to cigarette smoke for 4 or 11 days. Lung histology, bronchoalveolar lavage cell differentials, and expression of inflammatory and innate immune mediators in the lungs were assessed. MEASUREMENTS AND MAIN RESULTS: C/EBPβ was significantly down-regulated in the airway epithelium of both current and former smokers compared with never-smokers, and in cigarette smoke-treated primary human airway epithelial cells in vitro. Cigarette smoke-exposed mice with a lung epithelial-specific inactivation of C/EBPβ displayed blunted respiratory neutrophil influx and compromised induction of neutrophil chemoattractants growth-regulated oncogene-α, macrophage inflammatory protein-1γ, granulocyte colony-stimulating factor, and serum amyloid A 3 and proinflammatory cytokines tumor necrosis factor-α and interleukin-1β, compared with smoke-exposed controls. Inhibition of C/EBPβ in human airway cells in vitro caused a similarly compromised response to smoke. CONCLUSION: Our data suggest a previously unknown role for C/EBPβ and the airway epithelium in mediating inflammatory and innate immune responses to cigarette smoke.
RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease and lung cancer. The mechanisms by which smoking induces pulmonary dysfunction are complex, involving stress from toxic components and inflammatory responses. Although CCCAAT/enhancer-binding protein (C/EBP)-β is known as a key intracellular regulator of inflammatory signaling, its role in pulmonary inflammation has not been established. OBJECTIVES: To characterize the role of C/EBPβ in the airway epithelial response to cigarette smoke. METHODS: mRNA expression in the airway epithelium of current, former, and never-smokers, and in in vitro cigarette smoke extract-treated primary human airway epithelial cells, was analyzed by microarray and quantitative real-time polymerase chain reaction, respectively. Mice with lung epithelial-specific inactivation of C/EBPβ were generated and exposed to cigarette smoke for 4 or 11 days. Lung histology, bronchoalveolar lavage cell differentials, and expression of inflammatory and innate immune mediators in the lungs were assessed. MEASUREMENTS AND MAIN RESULTS: C/EBPβ was significantly down-regulated in the airway epithelium of both current and former smokers compared with never-smokers, and in cigarette smoke-treated primary human airway epithelial cells in vitro. Cigarette smoke-exposed mice with a lung epithelial-specific inactivation of C/EBPβ displayed blunted respiratory neutrophil influx and compromised induction of neutrophil chemoattractants growth-regulated oncogene-α, macrophage inflammatory protein-1γ, granulocyte colony-stimulating factor, and serum amyloid A 3 and proinflammatory cytokines tumor necrosis factor-α and interleukin-1β, compared with smoke-exposed controls. Inhibition of C/EBPβ in human airway cells in vitro caused a similarly compromised response to smoke. CONCLUSION: Our data suggest a previously unknown role for C/EBPβ and the airway epithelium in mediating inflammatory and innate immune responses to cigarette smoke.
Authors: Evelyn Tsantikos; Maverick Lau; Cassandra Mn Castelino; Mhairi J Maxwell; Samantha L Passey; Michelle J Hansen; Narelle E McGregor; Natalie A Sims; Daniel P Steinfort; Louis B Irving; Gary P Anderson; Margaret L Hibbs Journal: J Clin Invest Date: 2018-04-30 Impact factor: 14.808
Authors: Guo N Huang; Jeffrey E Thatcher; John McAnally; Yongli Kong; Xiaoxia Qi; Wei Tan; J Michael DiMaio; James F Amatruda; Robert D Gerard; Joseph A Hill; Rhonda Bassel-Duby; Eric N Olson Journal: Science Date: 2012-11-15 Impact factor: 47.728
Authors: David I Kasahara; Hye Y Kim; Joel A Mathews; Norah G Verbout; Alison S Williams; Allison P Wurmbrand; Fernanda M C Ninin; Felippe L Neto; Leandro A P Benedito; Christopher Hug; Dale T Umetsu; Stephanie A Shore Journal: Am J Physiol Lung Cell Mol Physiol Date: 2013-12-31 Impact factor: 5.464