PARP-1 inhibition provides protection against elastase-induced emphysema by mitigating the expression of matrix metalloproteinases
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In our previous study, we have shown that PARP-1 inhibition (genetic or pharmacological) ameliorates elastase-induced inflammation and emphysema. Since matrix metalloproteinases (MMPs) particularly MMP-2 and MMP-9 are known to play a critical role in emphysema development, the present work was designed to evaluate the effects of PARP-1 inhibition on their expression utilizing elastase-induced mouse model of emphysema. Our data show that olaparib administration at a dose of 5 mg/kg b.wt. (daily) significantly prevented the elastase-induced inflammation as indicated by decreased inflammatory cells particularly macrophages in BALF at 1 week post-injury. In addition, the drug restored the altered redox balance in the lungs of elastase-treated mice toward normal. Further, PCR data show that olaparib administration ameliorates the elastase-induced expression of MMP-2 and MMP-9 without having much effect on the expressions of their inhibitors TIMP-1 and TIMP-2. Next, our data on immunoblot, gelatin zymography, and immunohistochemical analysis indeed confirm that olaparib reduced the elastase-induced expression of MMP-2 and MMP-9. Reduction in the expression of metalloproteinases correlate well with the PARP activity as olaparib treatment suppressed the elastase-induced expression of PAR modified proteins markedly. Overall, our data strongly suggest that PARP-1 inhibition blunts elastase-induced MMP-2 and MMP-9 expression, which may be partly responsible for prevention of emphysema.
KeywordsElastase Emphysema MMPs Olaparib PARP-1
The financial assistance provided by the Department of Biotechnology, Government of India (BT/RLF/Re-entry/36/2012) (BT/PR/7968/MED/122/33/2016), DST-PURSE, and UGC-SAP to Dr. Amarjit Singh Naura is acknowledged. We also acknowledge the Senior Research Fellowships to Vivek Dharwal from CSIR.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest.
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