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

  • Vivek Dharwal
  • Rajat Sandhir
  • Amarjit S. NauraEmail author


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.


Elastase 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.

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)


  1. 1.
    Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, Lopez Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agusti A (2017) Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Respirology 22:575–601. CrossRefGoogle Scholar
  2. 2.
  3. 3.
    Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 187:347–365. CrossRefGoogle Scholar
  4. 4.
    MacNee W (2005) Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:258–266. discussion 290-1.CrossRefGoogle Scholar
  5. 5.
    Navratilova Z, Kolek V, Petrek M (2016) Matrix metalloproteinases and their inhibitors in chronic obstructive pulmonary disease. Arch Immunol Ther Exp (Warsz) 64:177–193. CrossRefGoogle Scholar
  6. 6.
    Churg A, Zhou S, Wright JL (2012) Series “matrix metalloproteinases in lung health and disease”: matrix metalloproteinases in COPD. Eur Respir J 39:197–209. CrossRefGoogle Scholar
  7. 7.
    Klein T, Bischoff R (2011) Physiology and pathophysiology of matrix metalloproteases. Amino Acids 41:271–290. CrossRefGoogle Scholar
  8. 8.
    Baraldo S, Bazzan E, Zanin ME, Turato G, Garbisa S, Maestrelli P, Papi A, Miniati M, Fabbri LM, Zuin R, Saetta M (2007) Matrix metalloproteinase-2 protein in lung periphery is related to COPD progression. Chest 132:1733–1740. CrossRefGoogle Scholar
  9. 9.
    Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M (2000) Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 117:684–694CrossRefGoogle Scholar
  10. 10.
    Vernooy JH, Lindeman JH, Jacobs JA, Hanemaaijer R, Wouters EF (2004) Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest 126:1802–1810. CrossRefGoogle Scholar
  11. 11.
    Li Y, Lu Y, Zhao Z, Wang J, Li J, Wang W, Li S, Song L (2016) Relationships of MMP-9 and TIMP-1 proteins with chronic obstructive pulmonary disease risk: a systematic review and meta-analysis. J Res Med Sci 21:12. CrossRefGoogle Scholar
  12. 12.
    Navratilova Z, Zatloukal J, Kriegova E, Kolek V, Petrek M (2012) Simultaneous up-regulation of matrix metalloproteinases 1, 2, 3, 7, 8, 9 and tissue inhibitors of metalloproteinases 1, 4 in serum of patients with chronic obstructive pulmonary disease. Respirology 17:1006–1012. CrossRefGoogle Scholar
  13. 13.
    Barnes PJ (2004) Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 56:515–548. CrossRefGoogle Scholar
  14. 14.
    Barnes PJ (2004) Alveolar macrophages as orchestrators of COPD. COPD 1:59–70. CrossRefGoogle Scholar
  15. 15.
    Kapellos TS, Bassler K, Aschenbrenner AC, Fujii W, Schultze JL (2018) Dysregulated functions of lung macrophage populations in COPD. J Immunol Res 2018:2349045. CrossRefGoogle Scholar
  16. 16.
    Butler A, Walton GM, Sapey E (2018) Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease. COPD. Google Scholar
  17. 17.
    Dharwal V, Naura AS (2018) PARP-1 inhibition ameliorates elastase induced lung inflammation and emphysema in mice. Biochem Pharmacol 150:24–34. CrossRefGoogle Scholar
  18. 18.
    Sahu B, Sandhir R, Naura AS (2018) Two hit induced acute lung injury impairs cognitive function in mice: a potential model to study cross talk between lung and brain. Brain Behav Immun 73:633–642. CrossRefGoogle Scholar
  19. 19.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  20. 20.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358 doi: 0003-2697(79)90738-3 [pii]CrossRefGoogle Scholar
  21. 21.
    Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–78. doi: 0304-4165(79)90289-7 [pii]CrossRefGoogle Scholar
  22. 22.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159. [pii]CrossRefGoogle Scholar
  23. 23.
    Sethi GS, Naura AS (2018) Progressive increase in allergen concentration abrogates immune tolerance in ovalbumin-induced murine model of chronic asthma. Int Immunopharmacol 60:121–131. CrossRefGoogle Scholar
  24. 24.
    Hans CP, Feng Y, Naura AS, Troxclair D, Zerfaoui M, Siddiqui D, Jihang J, Kim H, Kaye AD, Matrougui K, Lazartigues E, Boulares AH (2011) Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy. Cardiovasc Pathol 20:e57–e68. CrossRefGoogle Scholar
  25. 25.
    Andersen MP, Parham AR, Waldrep JC, McKenzie WN, Dhand R (2012) Alveolar fractal box dimension inversely correlates with mean linear intercept in mice with elastase-induced emphysema. Int J Chron Obstruct Pulmon Dis 7:235–243. CrossRefGoogle Scholar
  26. 26.
    Thurlbeck WM (1967) Internal surface area and other measurements in emphysema. Thorax 22:483–496CrossRefGoogle Scholar
  27. 27.
    One-way ANOVA followed by the Bonferroni multiple comparisons test was performed using GraphPad Prism version 5.01 for Windows, GraphPad Software, La Jolla California USA.
  28. 28.
    Kirkham PA, Barnes PJ (2013) Oxidative stress in COPD. Chest 144:266–273. CrossRefGoogle Scholar
  29. 29.
    Tetley TD (2002) Macrophages and the pathogenesis of COPD. Chest 121:156S -159S. doi: S0012-3692(15)35382-4CrossRefGoogle Scholar
  30. 30.
    Meijer M, Rijkers GT, van Overveld FJ (2013) Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease. Expert Rev Clin Immunol 9:1055–1068. CrossRefGoogle Scholar
  31. 31.
    Sethi GS, Dharwal V, Naura AS (2017) Poly(ADP-ribose)polymerase-1 in lung inflammatory disorders: a review. Front Immunol 8:1172. CrossRefGoogle Scholar
  32. 32.
    Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL (2007) Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 62:706–713. CrossRefGoogle Scholar
  33. 33.
    Castaneda FE, Walia B, Vijay-Kumar M, Patel NR, Roser S, Kolachala VL, Rojas M, Wang L, Oprea G, Garg P, Gewirtz AT, Roman J, Merlin D, Sitaraman SV (2005) Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 129:1991–2008. CrossRefGoogle Scholar
  34. 34.
    Corry DB, Kiss A, Song LZ, Song L, Xu J, Lee SH, Werb Z, Kheradmand F (2004) Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J 18:995–997. CrossRefGoogle Scholar
  35. 35.
    Manicone AM, McGuire JK (2008) Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol 19:34–41. CrossRefGoogle Scholar
  36. 36.
    Mohan MJ, Seaton T, Mitchell J, Howe A, Blackburn K, Burkhart W, Moyer M, Patel I, Waitt GM, Becherer JD, Moss ML, Milla ME (2002) The tumor necrosis factor-alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Biochemistry 41:9462–9469CrossRefGoogle Scholar
  37. 37.
    English WR, Puente XS, Freije JM, Knauper V, Amour A, Merryweather A, Lopez-Otin C, Murphy G (2000) Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem 275:14046–14055. doi: 275/19/14046CrossRefGoogle Scholar
  38. 38.
    Schonbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161:3340–3346Google Scholar
  39. 39.
    Senior RM, Griffin GL, Mecham RP (1980) Chemotactic activity of elastin-derived peptides. J Clin Investig 66:859–862. CrossRefGoogle Scholar
  40. 40.
    Adair-Kirk TL, Senior RM (2008) Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol 40:1101–1110. CrossRefGoogle Scholar
  41. 41.
    Lagente V, Manoury B, Nenan S, Le Quement C, Martin-Chouly C, Boichot E (2005) Role of matrix metalloproteinases in the development of airway inflammation and remodeling. Braz J Med Biol Res 38:1521–1530 doi: S0100-879X2005001000009CrossRefGoogle Scholar
  42. 42.
    Ghorai A, Sarma A, Chowdhury P, Ghosh U (2016) PARP-1 depletion in combination with carbon ion exposure significantly reduces MMPs activity and overall increases TIMPs expression in cultured HeLa cells. Radiat Oncol 11:126. CrossRefGoogle Scholar
  43. 43.
    Chen T, Wang W, Li JR, Xu HZ, Peng YC, Fan LF, Yan F, Gu C, Wang L, Chen G (2016) PARP inhibition attenuates early brain injury through NF-kappaB/MMP-9 pathway in a rat model of subarachnoid hemorrhage. Brain Res 1644:32–38. CrossRefGoogle Scholar
  44. 44.
    Barnes PJ (2006) Transcription factors in airway diseases. Lab Investig 86:867–872. CrossRefGoogle Scholar
  45. 45.
    Rhee JW, Lee KW, Kim D, Lee Y, Jeon OH, Kwon HJ, Kim DS (2007) NF-kappaB-dependent regulation of matrix metalloproteinase-9 gene expression by lipopolysaccharide in a macrophage cell line RAW 264.7. J Biochem Mol Biol 40:88–94Google Scholar
  46. 46.
    Lan YQ, Zhang C, Xiao JH, Zhuo YH, Guo H, Peng W, Ge J (2009) Suppression of IkappaBalpha increases the expression of matrix metalloproteinase-2 in human ciliary muscle cells. Mol Vis 15:1977–1987Google Scholar
  47. 47.
    Abd Elmageed ZY, Naura AS, Errami Y, Zerfaoui M (2012) The poly(ADP-ribose) polymerases (PARPs): new roles in intracellular transport. Cell Signal 24:1–8. CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of BiochemistryPanjab UniversityChandigarhIndia

Personalised recommendations