Novel molecular pathologies in asthma and COPD

Both asthma and COPD are respiratory diseases and a major global health problem with
increasing prevalence. Airway inflammation is a characteristic and important hallmark in both
diseases and therefore, in the past, investigations focused strongly on the immunological aspect of
these disorders.
In recent years, it has been shown that resident cells of the airways, in particular airway smooth
muscle (ASM) cells, would be pivotal in understanding the mechanisms underlying asthma, since
they are able to secrete pro-inflammatory cytokines and exert a major effector function in airway
constriction. Especially the abnormal expression in ASM cells in asthmatic patients of the cell
cycle regulator and pro-inflammatory gene transcription factor C/EBPα may account for many
asthma-specific phenotypes (increased proliferation and increased bulk of ASM cells, increased
release of inflammatory mediators).
In a first phase, we analyzed the translation of the CEBPA mRNA with a translation control
reporter system (TCRS), which is able to monitor translation regulation of the C/EBPα. We found
an impaired translation re-initiaion in ASM cells of asthmatic patients, which coincided with
decreased 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 mite
extract, a potent airborne allergen. We found that HDM extract (i) reduces C/EBPα expression in
ASM 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 repressor
of CEBPA mRNA translation. Therefore, the direct, not immune-mediated interaction of HDM
extract with the ASM cells is able to trigger an inflammatory response in these cells and to induce
an 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 to
explain non-atopic, intrinsic asthma, which affects 30% - 50% of asthmatic subjects. In the light
of these findings, new therapeutic strategies targeting regulatory mechanisms of CEBPA mRNA
translation 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 levels
of 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 serumfree
environment, cigarette smoke increased both C/EBPα and -β expression at the translational
level via the uORF mechanism. In the presence of FCS, cigarette smoke increased the levels of
hnRNP E2, an inhibitor of C/EBPα translation. As a consequence, both C/EBPα and -β
expression decreased with increasing concentration of cigarette smoke. In both conditions,
cigarette smoke had a potent antiproliferative effect on fibroblasts. Furthermore, cigarette smoke
increased the release of IL-8. We postulate that the cigarette smoke-induced imbalance of proand
anti-proliferative signals provides a novel mechanism to explain many pathologies of COPD
and emphysema, especially the tissue destruction defined as an imbalance between tissue injury
and tissue repair. Furthermore, we showed that that the direct interaction of lung fibroblast with
cigarette smoke triggers the release of pro-inflammatory mediators, contributing to the
inflammatory environment that characterizes COPD.