Intracellular signaling in the lung : A role for C/EBP transcription factors in chronic obstructive pulmonary disease, glucocorticoid signaling and lung development

摘要: Over the last decade, a previously unknown role has been established for members of C/EBP transcription factor family in lung gene expression. In other organs, C/EBPs are well known regulators cell differentiation and linked processes such as proliferation, apoptosis, expression central inflammatory responses infectious defenses. The scope this thesis is to investigate factors human mouse putative pathogenesis chronic obstructive pulmonary disease (COPD). As first approach, DNA-binding activity was studied airway epithelium humans adult mice. We found that C/EBPβ dominant factor. Interestingly, we also C/EBPβ-activity increased airways asymptomatic smokers, whereas smokers develop COPD lack increase. hypothesize altered epithelial cells COPD. Here it could affect production mediators genes involved anti-oxidative defenses addition affecting thereby making lungs more susceptible destruction inflammation which augment progression disease. Inflammation typically exhibits partial resistance anti-inflammatory action glucocorticoids. When studying glucocorticoid signaling epithelium, receptor, at least partially, mediates effects glucocorticoids by inducing phosphorylation C/EBPβ, augmenting its activity. This raises possibility decrease C/EBP-binding patients with may have causative relative seen means deepen our understanding family’s lung, critically address whether related pathological processes, an animal model used due limitations sampling lung. approach evaluate suitable study functions investigated C/ EBPs patients. By using immunohistochemistry pattern highly similar C/EBPα suggesting addition, displays dynamic during development together respiratory distress neonatal knockout mice, suggest crucial generated gain-offunction ectopically expressing (SFTPC-Cebpa mice), lossof-function Cre-LoxP technique, disruption (CebpaΔLE mice) hypothesis. Both CebpaΔLE mice FTPC-Cebpa display strikingly impaired phenotypes characterized decreased number growing tubules larger size thickened interstitsium, indicating tempo-spatial important correct development. Further, survive perinatal lethality, demonstrate severe picture 1) goblet hyperplasia, bronchiolar metaplasia, fibrosis mucus plugging, pathologically defined bronchiolitis, 2) emphysema 3) extensive macrophage lymphocyte infiltrations. vital differentiation. Repair generally descend from mechanisms pathways organ or tissue Therefore, potential remodeling either inadequate. diagnosis based on clinical, radiological functional features but there well-recognized histopathological correlates including all findings line this, tempting speculate share some underlying mechanisms, linkage between differentiation-repair process inherent summary, presented investigations provide knowledge, potentially serve base new treatments devastating LIST OF PUBLICATIONS I. Didon, L., Qvarfordt, I.. Andersson, O., Nord, M. Riise, GC. Decreased CCAAT/Enhancer Binding Protein Transcription Factor Activity Chronic Bronchitis Chest 127(4): 1341-6. 2005. II. Berg, T.*, L.*, Barton, J., O. Glucocorticoids increase C/EBPbeta via phosphorylation. Biochemical Biophysical Research Communications 334(2): 638-45. 2005 (*these authors contributed equally) III. T., Ectopic transgenic C/EBPalpha disrupts late American Journal Physiology (Lung Cell Molecular Physiology). 291(4): 683-93. 2006. IV. Elmberger, G., Gonzalez, F. J. & Adult lung-specific inactivation emphysematic phenotype epithelium. Submitted. Publications not included thesis: L. recognition receptor Nod1 activates CCAAT/enhancer binding protein beta signalling cells. Eur Respir J 30: 214-222. 2007.