Abstract
Emphysema is characterized by alveolar wall destruction induced mainly by cigarette smoke. Oxidative damage of DNA may contribute to the pathophysiology of this disease. We studied the impairment of the non-homologous end joining (NHEJ) repair pathway and DNA damage in alveolar type II (ATII) cells and emphysema development. We isolated primary ATII cells from control smokers, nonsmokers, and patients with emphysema to determine DNA damage and repair. We found higher reactive oxygen species generation and DNA damage in ATII cells obtained from individuals with this disease in comparison with controls. We also observed low phosphorylation of H2AX, which activates DSBs repair signaling, in emphysema. Our results indicate the impairement of NHEJ, as detected by low XLF expression. We also analyzed the role of DJ-1, which has a cytoprotective activity. We detected DJ-1 and XLF interaction in ATII cells in emphysema, which suggests the impairment of their function. Moreover, we found that DJ-1 KO mice are more susceptible to DNA damage induced by cigarette smoke. Our results suggest that oxidative DNA damage and ineffective the DSBs repair via the impaired NHEJ may contribute to ATII cell death in emphysema.
Highlights
Emphysema belongs to chronic obstructive pulmonary disease (COPD)
Since decreased alveolar type II (ATII) cell proliferation and increased ATII cell death have been recently observed in COPD patients[26], we wanted to determine ROS production in freshly isolated ATII cells from individuals with emphysema
We observed decreased XLF protein (Fig. 3I,J) and mRNA levels (Fig. 3K) in ATII cells in individuals with this disease. These results indicate that ATII cells in emphysema have an impaired classical Non-homologous end-joining (NHEJ) pathway, which causes ineffective repair of DNA damage leading to cell death
Summary
Emphysema belongs to chronic obstructive pulmonary disease (COPD). Cigarette smoke is a main risk factor of this disease development[1]. DNA double strand breaks (DSBs) can be caused by oxidative stress[14] They activate DNA repair mechanisms to eliminate DNA damage. We showed that ATII cells isolated from heavy smokers and emphysema patients have high oxidative stress levels and apoptosis This was correlated with the impairment of the DJ-1 protective activity. We analyzed expression of proteins involved in both alternative and classical NHEJ pathways to determine the efficiency of DNA damage repair in ATII cells under high oxidative stress in this disease. We identified DJ-1 as a novel interaction partner of XLF in ATII cells in emphysema We hypothesize that this interaction may inhibit ROS scavenging function of DJ-1, leading to high oxidative DNA damage, the impairment of the NHEJ repair pathway, ATII cell death and this disease development
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