Cigarette smoking is the major risk factor for pulmonary emphysema, a critical phenotype of chronic obstructive pulmonary disease (COPD). However, it remains unclear why emphysema persists despite smoking cessation. Emerging evidence suggests a potential role of persistent DNA damage due to DNA repair insufficiency. Our novel preliminary data determined that protein expression of the DNA repair gene XRCC5 is markedly reduced and associated with increased small ubiquitin-related modifier conjugation (SUMOylation) in the lungs of patients with COPD. Cigarette smoke extract (CSE) significantly decreased XRCC5 protein, but not mRNA, in primary human bronchoepithelial cells (HBECs). Suppression of XRCC5 expression augmented CSE-induced cytotoxicity and DNA damage (?H2AX) in immortalized HBECs. By contrast, XRCC5 overexpression attenuated the CSE effects. Furthermore, the hemizygous deficiency of XRCC5 augmented emphysema in response to cigarette smoke (CS) and influenza virus (IAV) infection. These preliminary data led us to an overarching hypothesis that CS-induced depletion of the critical repair protein, XRCC5, contributes to persistent DNA damage and the formation of emphysema.
In Aim 1, we will determine whether the lungs of ex-smokers with COPD exhibit XRCC5 loss and DNA damage compared with ex-smokers without COPD.
In Aim 2, the mechanisms of CS-induced depletion of XRCC5 in vitro will be investigated.
In Aim 3, to determine whether XRCC5 protein expression modulates CS-induced DNA damage and emphysema, we will execute loss-of-function and gain-of-function studies of XRCC5 in vivo using XRCC5+/- and XRCC5 transgenic mice, respectively. By achieving these aims, we will deepen our understanding of the role of DNA repair in COPD pathogenesis. These findings may lead to the development of novel therapeutics by augmenting DNA repair (e.g., XRCC5) that may modulate susceptibility to CS-induced emphysema.

Public Health Relevance

Why does COPD persist despite smoking cessation? Emerging evidence suggests a potential role of persistent DNA damage due to DNA repair deficiency. However, the causative role of unbalanced DNA damage and repair is unclear. This proposal will investigate the role of DNA repair in COPD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
7I01CX001048-02
Application #
9000005
Study Section
Respiration (PULM)
Project Start
2015-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
033127569
City
Pittsburgh
State
PA
Country
United States
Zip Code
15240