Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ...

Pulmonary and Systemic Cellular Markers of Repair, Regeneration and
Senescence in COPD.
M. Kumar 1 , N. Weissman 2 , W. Seeger 1, 2 , R. Voswinckel 1
1 Max-Planck-Institute for Heart and Lung Research, Dept. of Lung Development and Remodeling,
Bad Nauheim; 2 UGMLC, Universities of Gießen and Marburg Lung Centre
Introduction: Pulmonary emphysema is an age-related disease of the lungs. It occurs after a
prolonged period of cigarette smoking. Deregulated repair, tissue regeneration and lung regression
are the hallmarks of COPD. Cellular senescence is a signal transduction program leading to
irreversible cell cycle arrest. The growth arrest can be triggered by many different mechanisms
including recognition by cellular sensors of DNA double-strand breaks leading to the activation of cell
cycle checkpoint responses and recruitment of DNA repair foci. The execution of regenerative
programs in lung and remote organs is closely linked to viability or senescence of resident cells as
well as progenitor cells derived from the circulation. We propose COPD to be a disease of premature
lung senescence and aim to decipher markers of DNA damage, repair and senescence in smokers
with and without COPD as well as in animal models of smoke induced emphysema.
Results: Cellular senescence could be successfully assessed by staining for β-galactosidase and
evaluation of senescence associated heterochromatin foci (SAHF), reflecting condensed chromatin, in
the nuclei. DNA double strand breaks and cell cycle arrest could be demonstrated by up regulated 53-
BP1 and p21.
In vitro, senescence of fibroblasts of lung could be induced by 100uM H 2 O 2 as well as by 1% cigarette
smoke extract. PBMC derived Circulating fibrocytes were rather stimulated in growth by H 2 O 2 than
driven towards senescence.
Paraffin sections from Human COPD samples were investigated for markers of senescence, DNA
damage and repair. Markers of DNA damage and senescence seem to be prominently up regulated in
the diseased samples. Preliminary studies on smoking mouse models for emphysema suggests
similar conclusions. More experiments on a larger sample size are in progress.
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