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- W1569291408 abstract "Over the last decade, a previously unknown role has been established for members of the C/EBP transcription factor family in lung gene expression. In other organs, C/EBPs are well known regulators of cell differentiation and linked processes such as proliferation, apoptosis, gene expression as well as central regulators of inflammatory responses and infectious defenses. The scope of this thesis is to investigate the role of C/EBP transcription factors in the human and mouse lung as well as a putative role in the pathogenesis of chronic obstructive pulmonary disease (COPD). As a first approach, DNA-binding activity of C/EBPs was studied in the airway epithelium of humans and in adult mice. We found that C/EBPβ is the dominant DNA-binding C/EBP transcription factor. Interestingly, we also found that C/EBPβ-activity is increased in the airways of asymptomatic smokers, whereas smokers that develop COPD lack this increase. We hypothesize that altered activity of C/EBPβ in airway epithelial cells has a previously unknown role in the pathogenesis of COPD. Here it could affect the production of inflammatory mediators and genes involved in anti-oxidative and infectious defenses in addition to affecting epithelial cell proliferation, thereby making the lungs more susceptible to destruction and inflammation which augment the progression of the disease. Inflammation in COPD typically exhibits partial resistance to the anti-inflammatory action of glucocorticoids. When studying glucocorticoid signaling in the lung epithelium, we found that the glucocorticoid receptor, at least partially, mediates the effects of glucocorticoids in lung epithelium by inducing phosphorylation of C/EBPβ, thereby augmenting its DNA-binding activity. This raises the possibility that the decrease in C/EBP-binding activity in the airway epithelium of patients with COPD may have a causative role for the relative resistance to glucocorticoids seen in this disease. As a means to deepen our understanding of the C/EBP family’s role in the lung, as well as to critically address whether C/EBPs have a role in COPD pathogenesis and related pathological processes, an animal model was used due to the limitations in sampling the human lung. As a first approach to evaluate whether the mouse is a suitable model to study C/EBP functions in the lung, we investigated the expression of C/ EBPs in the human and mouse lung epithelium in addition to the lung epithelium of COPD patients. By using immunohistochemistry we found that the adult expression pattern of C/EBPs in the mouse lung is highly similar to the expression pattern of C/EBPα and C/EBPβ in the human lung, suggesting the mouse as a suitable model to study the C/EBP family’s role in lung. In addition, we found that C/EBPα displays dynamic expression during lung development that together with the respiratory distress of neonatal C/EBPα knockout mice, suggest a crucial role for C/EBPα in the development of the lung. We generated a gain-offunction mouse model ectopically expressing C/EBPα in the lung epithelium (SFTPC-Cebpa mice), and a lossof-function mouse model using the Cre-LoxP technique, with lung epithelial disruption of the C/EBPα gene (CebpaΔLE mice) to address this hypothesis. Both CebpaΔLE mice and FTPC-Cebpa mice display strikingly similar impaired lung phenotypes during development characterized by a decreased number of growing epithelial tubules which are larger in size as well as a thickened interstitsium, indicating that the tempo-spatial expression of C/EBPα is important for correct lung development. Further, adult CebpaΔLE mice, that survive the perinatal lethality, demonstrate a severe pathological picture with 1) goblet cell hyperplasia, bronchiolar metaplasia, fibrosis and mucus plugging, together pathologically defined as bronchiolitis, 2) emphysema and 3) extensive macrophage and lymphocyte infiltrations. C/EBPα has a vital role in lung development and lung epithelial differentiation. Repair processes generally descend from mechanisms and signaling pathways used during organ or tissue development. Therefore, C/EBPα could have a potential role also in remodeling processes, which in COPD patients either is impaired or inadequate. The diagnosis of COPD is based on clinical, radiological and functional features but there are well-recognized histopathological correlates including all the histopathological findings in the CebpaΔLE mice. In line with this, it is tempting to speculate that the pathological processes in COPD and CebpaΔLE mice share at least some underlying mechanisms, with a linkage between the epithelial differentiation-repair process inherent in COPD and the epithelial differentiation during lung development. In summary, the findings presented in this thesis suggest that investigations of the role of C/EBPs in the pathogenesis of COPD could provide important knowledge, that may potentially serve as a base for the development of new treatments for this devastating disease. LIST OF PUBLICATIONS I. Didon, L., Qvarfordt, I.. Andersson, O., Nord, M. and Riise, GC. Decreased CCAAT/Enhancer Binding Protein Transcription Factor Activity in Chronic Bronchitis and COPD. Chest 127(4): 1341-6. 2005. II. Berg, T.*, Didon, L.*, Barton, J., Andersson, O. and Nord, M. Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochemical and Biophysical Research Communications 334(2): 638-45. 2005 (*these authors contributed equally) III. Berg, T., Didon, L., and Nord, M. Ectopic transgenic expression of C/EBPalpha in the lung epithelium disrupts late lung development. American Journal of Physiology (Lung Cell and Molecular Physiology). 291(4): 683-93. 2006. IV. Didon, L., Elmberger, G., Gonzalez, F. J. & Nord, M. Adult mice with a lung-specific inactivation of the transcription factor C/EBPalpha develop an emphysematic lung phenotype with impaired differentiation of the respiratory epithelium. Submitted. Publications not included in the thesis: Barton, J. L., Berg, T., Didon, L. and Nord, M. The pattern recognition receptor Nod1 activates CCAAT/enhancer binding protein beta signalling in lung epithelial cells. Eur Respir J 30: 214-222. 2007." @default.
- W1569291408 created "2016-06-24" @default.
- W1569291408 creator A5016084475 @default.
- W1569291408 date "2008-05-23" @default.
- W1569291408 modified "2023-09-23" @default.
- W1569291408 title "Intracellular signaling in the lung : A role for C/EBP transcription factors in chronic obstructive pulmonary disease, glucocorticoid signaling and lung development" @default.
- W1569291408 cites W14778716 @default.
- W1569291408 cites W1489079707 @default.
- W1569291408 cites W1512960324 @default.
- W1569291408 cites W1522814938 @default.
- W1569291408 cites W1528349601 @default.
- W1569291408 cites W153904168 @default.
- W1569291408 cites W1589308530 @default.
- W1569291408 cites W1648092828 @default.
- W1569291408 cites W1703656775 @default.
- W1569291408 cites W1768274470 @default.
- W1569291408 cites W179818011 @default.
- W1569291408 cites W1844026860 @default.
- W1569291408 cites W1877755747 @default.
- W1569291408 cites W1881536029 @default.
- W1569291408 cites W1906119900 @default.
- W1569291408 cites W1933156589 @default.
- W1569291408 cites W1939477527 @default.
- W1569291408 cites W1963246255 @default.
- W1569291408 cites W1963272169 @default.
- W1569291408 cites W1965237664 @default.
- W1569291408 cites W1965940540 @default.
- W1569291408 cites W1967290172 @default.
- W1569291408 cites W1967364632 @default.
- W1569291408 cites W1968112541 @default.
- W1569291408 cites W1968424865 @default.
- W1569291408 cites W1969502320 @default.
- W1569291408 cites W1973742535 @default.
- W1569291408 cites W1974609791 @default.
- W1569291408 cites W1978855332 @default.
- W1569291408 cites W1980946495 @default.
- W1569291408 cites W1981681632 @default.
- W1569291408 cites W1983683479 @default.
- W1569291408 cites W1984540916 @default.
- W1569291408 cites W1984862476 @default.
- W1569291408 cites W1987598864 @default.
- W1569291408 cites W1991170665 @default.
- W1569291408 cites W1991185272 @default.
- W1569291408 cites W1993296518 @default.
- W1569291408 cites W1996616149 @default.
- W1569291408 cites W1997510672 @default.
- W1569291408 cites W1998224383 @default.
- W1569291408 cites W1999226863 @default.
- W1569291408 cites W2000071183 @default.
- W1569291408 cites W2000195300 @default.
- W1569291408 cites W2000720532 @default.
- W1569291408 cites W2003028861 @default.
- W1569291408 cites W2003693532 @default.
- W1569291408 cites W2004556227 @default.
- W1569291408 cites W2005668937 @default.
- W1569291408 cites W2006813853 @default.
- W1569291408 cites W2008493932 @default.
- W1569291408 cites W2008779719 @default.
- W1569291408 cites W2009869521 @default.
- W1569291408 cites W2010133641 @default.
- W1569291408 cites W2010648372 @default.
- W1569291408 cites W2011582754 @default.
- W1569291408 cites W2011791283 @default.
- W1569291408 cites W2011876371 @default.
- W1569291408 cites W2012858641 @default.
- W1569291408 cites W2013571070 @default.
- W1569291408 cites W2013575704 @default.
- W1569291408 cites W2016557214 @default.
- W1569291408 cites W2016576925 @default.
- W1569291408 cites W2016797740 @default.
- W1569291408 cites W2017338099 @default.
- W1569291408 cites W2017386008 @default.
- W1569291408 cites W2017429814 @default.
- W1569291408 cites W2018235995 @default.
- W1569291408 cites W2019593536 @default.
- W1569291408 cites W2021861489 @default.
- W1569291408 cites W2022184429 @default.
- W1569291408 cites W2025218389 @default.
- W1569291408 cites W2026451392 @default.
- W1569291408 cites W2026554087 @default.
- W1569291408 cites W2027062206 @default.
- W1569291408 cites W2027416180 @default.
- W1569291408 cites W2028244297 @default.
- W1569291408 cites W2028896067 @default.
- W1569291408 cites W2031272783 @default.
- W1569291408 cites W2031867175 @default.
- W1569291408 cites W2033585099 @default.
- W1569291408 cites W2034200840 @default.
- W1569291408 cites W2034545406 @default.
- W1569291408 cites W2038094327 @default.
- W1569291408 cites W2038912397 @default.
- W1569291408 cites W2040557727 @default.
- W1569291408 cites W2040950523 @default.
- W1569291408 cites W2041165461 @default.
- W1569291408 cites W2042500137 @default.
- W1569291408 cites W2046390517 @default.
- W1569291408 cites W2048789360 @default.
- W1569291408 cites W2049363328 @default.
- W1569291408 cites W2049629344 @default.
- W1569291408 cites W2049855336 @default.