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PARP-1 inhibition provides protection against elastase-induced emphysema by mitigating the expression of matrix metalloproteinases

  • Vivek Dharwal
  • Rajat Sandhir
  • Amarjit S. NauraEmail author
Article
  • 56 Downloads

Abstract

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.

Keywords

Elastase Emphysema MMPs Olaparib PARP-1 

Notes

Acknowledgements

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.

Supplementary material

11010_2019_3510_MOESM1_ESM.pptx (102 kb)
Supplementary material 1 For Supplementary data: (A) Serum glutamic-pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) activities (as marker of liver functions) were assessed in different groups of mice sacrificed 21 days after elastase administration. Our data show that olaparib treatment did cause any toxicity. (ns- nonsignificant w.r.t control group.) (B) Biochemical assays were performed in total lung homogenates of mice sacrificed 21 days after elastase administration. Level of ROS, MDA, and GSH were analyzed. (* significant w.r.t control group p < 0.05, # significant w.r.t elastase group p < 0.05.) (PPTX 101 KB)

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of BiochemistryPanjab UniversityChandigarhIndia

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