PARP-1 inhibition ameliorates elastase induced lung inflammation and emphysema in mice.

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Journal Article
Biochem Pharmacol, 2018, 150, pp. 24-34
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COPD is associated with high morbidity and mortality and no effective treatment is available till date. We have previously reported that PARP-1 plays an important role in the establishment of airway inflammation associated with asthma and ALI. In the present work, we have evaluated the beneficial effects of PARP-1 inhibition on COPD pathogenesis utilizing elastase induced mouse model of the disease. Our data show that PARP-1 inhibition by olaparib significantly reduced the elastase-induced recruitment of inflammatory cells particularly neutrophils in the lungs of mice when administered at a dose of 5 mg/kg b.wt (i.p.). Reduction in the lung inflammation was associated with suppressed myeloperoxidase activity. Further, the drug restored the redox status in the lung tissues towards normal as reflected by the levels of ROS, GSH and MDA. Olaparib administration prior to elastase instillation blunted the phosphorylation of P65-NF-κB at Ser 536 without altering phosphorylation of its inhibitor IκBα in the lungs. Furthermore, olaparib down regulated the elastase-induced expression of NF-κB dependent pro-inflammatory cytokines (TNF-A, IL-6), chemokine (MIP-2) and growth factor (GCSF) severely both at the mRNA and protein levels. Additionally, PARP-1 heterozygosity suppressed the recruitment of inflammatory cells and production of TNF-A, IL-6, MIP-2 and GCSF in the BALF to the similar extent as exhibited by olaparib administration. Finally, PARP-1 inhibition by olaparib or gene deletion protected against elastase-induced emphysema markedly. Overall, our data strongly suggest that PARP-1 plays a critical role in elastase induced lung inflammation and emphysema, and thus may be a new drug target candidate in COPD.
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