Increased DNA damage due to

Increased DNA damage due to enhanced oxidative stress has been reported in patients with COPD. Ceylan et al. and Maluf et al. reported that DNA damage is increased in the PBMCs from patients with COPD as compared to healthy individuals [69], [70]. Similar results were found in a study involving lung tissue samples from patient with COPD. It was reported that double strand DNA breaks were higher in alveolar type I, II cells, and endothelial Topotecan HCl sale in the COPD patients when compared to asymptomatic smokers and nonsmokers [24]. In consideration of increased DNA damage in COPD, the concomitant elevation in the activity of DNA repair enzyme, PARP-1, has also been reported. Hageman et al. reported the systemic activation of PARP-1 as the percentage of PAR positive lymphocyte was found to be significantly higher in the patients with COPD when compared to the healthy individuals [27]. Recently it has been reported that levels of the DNA damage, PARP-1 activity, and PARP-1 mRNA expression in PBMCs correlate well with progression as well as exacerbation of COPD [26]. Our data also strongly suggest that reduction in lung inflammation and oxidative stress in the tissue by olaparib was closely associated with the suppression of PARP activity. The redox sensitive transcription factor NF-κB is reported to play a crucial role in the COPD pathogenesis via up regulating the expression of several cytokines, chemokines, growth factors, and adhesion molecules [71]. Incidentally, we and others have shown that PARP-1 modulates the NF-κB activation for efficient expression of several pro-inflammatory factors [18], [21], [72]. Analysis of NF-κB activation in present model showed that olaparib blocks the NF-κB activation through suppression of phosphorylation of P65NF-κB at ser 532 without altering the phosphorylation of IκBα. Furthermore, PARP-1 inhibition reduced the mRNA expression of NF-κB dependent pro inflammatory cytokines (TNF-Α, IL-6), chemokine (MIP-2; mouse analogue of IL-8) and growth factor (GCSF). The reduction in the mRNA expression of such genes was corroborated by their reduced production at the protein level in BALF. These cytokines play a crucial role in establishment of COPD associated inflammation. In fact, the elevated levels of TNF-Α, IL-6, and/or IL-8 in serum or BALF are considered as a hallmark of the disease [45], [46]. Different studies have shown that TNF-Α depletes cellular GSH content in pulmonary tissues [73], [74]. Additionally, it is reported that TNF-Α stimulates ROS production in human endothelial cells and neutrophils [75], [76]. The expression of adhesion molecules, which is required for infiltration of inflammatory cells in the lungs, is known to be influenced by TNF-Α [77], [78], [79]. IL-8 is the primary chemokine that is associated with chemotactic response of neutrophils. GCSF is an important growth factor that is associated with survival and proliferation of neutrophils [47]. Additionally, we observed that PARP-1 inhibition was associated with reduced expression of cell adhesion molecules ICAM-1 and VCAM-1.