Chronic obstructive pulmonary disease (COPD) is an age-associated disease caused mainly by cigarette smoking. Deregulated repair, tissue destruction, inflammation 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 several different mechanisms, including recognition of DNA double-strand breaks by cellular sensors, leading to the activation of cell cycle checkpoint responses and recruitment of DNA repair machinery to damaged 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. It was proposed here, that COPD might be a disease of premature lung senescence and therefore this work aimed to decipher markers of DNA damage, repair and senescence in lung cell culture and a murine model of cigarette smoke induced emphysema.In-vitro, cellular senescence could be successfully assessed by staining for beta-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, gammaH2AX and p21. Paraffin lung sections from mice exposed to cigarette smoke were investigated for markers of cellular senescence, DNA damage and repair. Markers of DNA double strand breaks and senescence were up regulated in a time dependent manner, showing a correlation of DNA damage and emphysema progression. These results indicated that the pulmonary senescence in COPD is linked with persistent DNA double-strand breaks due to prolonged cigarette smoking.
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