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• W1519932232 abstract "Both asthma and COPD are respiratory diseases and a major global health problem withincreasing prevalence. Airway inflammation is a characteristic and important hallmark in bothdiseases and therefore, in the past, investigations focused strongly on the immunological aspect ofthese disorders.In recent years, it has been shown that resident cells of the airways, in particular airway smoothmuscle (ASM) cells, would be pivotal in understanding the mechanisms underlying asthma, sincethey are able to secrete pro-inflammatory cytokines and exert a major effector function in airwayconstriction. Especially the abnormal expression in ASM cells in asthmatic patients of the cellcycle regulator and pro-inflammatory gene transcription factor C/EBPα may account for manyasthma-specific phenotypes (increased proliferation and increased bulk of ASM cells, increasedrelease of inflammatory mediators).In a first phase, we analyzed the translation of the CEBPA mRNA with a translation controlreporter system (TCRS), which is able to monitor translation regulation of the C/EBPα. We foundan impaired translation re-initiaion in ASM cells of asthmatic patients, which coincided withdecreased levels of eIF4E, an important protein for translation initiation.In a second part of this thesis, we investigated the interaction of ASM cells with house dust miteextract, a potent airborne allergen. We found that HDM extract (i) reduces C/EBPα expression inASM cells of asthma patients, (ii) enhances the release of IL-6 and (iii) induces cell proliferation.The reduction of the C/EBPα protein is achieved trough up-regulation of calreticulin, a repressorof CEBPA mRNA translation. Therefore, the direct, not immune-mediated interaction of HDMextract with the ASM cells is able to trigger an inflammatory response in these cells and to inducean enhanced proliferation, which may finally lead to the characteristic increased muscle mass observed in the airway of asthmatic patients. These findings may be of particular importance toexplain non-atopic, intrinsic asthma, which affects 30% - 50% of asthmatic subjects. In the lightof these findings, new therapeutic strategies targeting regulatory mechanisms of CEBPA mRNAtranslation should be considered in order to restore a balanced expression of the C/EBPα protein.In a third part of this thesis, we investigated the effect of cigarette smoke on the expression levelsof C/EBPα and C/EBPβ in primary lung fibroblasts. Cigarette smoke affects both C/EBPα and C/EBPβ expression via translational control mechanisms in primary lung fibroblasts. In serumfreeenvironment, cigarette smoke increased both C/EBPα and -β expression at the translationallevel via the uORF mechanism. In the presence of FCS, cigarette smoke increased the levels ofhnRNP E2, an inhibitor of C/EBPα translation. As a consequence, both C/EBPα and -βexpression decreased with increasing concentration of cigarette smoke. In both conditions,cigarette smoke had a potent antiproliferative effect on fibroblasts. Furthermore, cigarette smokeincreased the release of IL-8. We postulate that the cigarette smoke-induced imbalance of proandanti-proliferative signals provides a novel mechanism to explain many pathologies of COPDand emphysema, especially the tissue destruction defined as an imbalance between tissue injuryand tissue repair. Furthermore, we showed that that the direct interaction of lung fibroblast withcigarette smoke triggers the release of pro-inflammatory mediators, contributing to theinflammatory environment that characterizes COPD." @default.
• W1519932232 created "2016-06-24" @default.
• W1519932232 creator A5034441927 @default.
• W1519932232 date "2010-01-01" @default.
• W1519932232 modified "2023-09-27" @default.
• W1519932232 title "Novel molecular pathologies in asthma and COPD" @default.
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