Molecular and Cellular Biochemistry

, Volume 400, Issue 1–2, pp 153–162 | Cite as

PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice

  • Kunal Kapoor
  • Esha Singla
  • Bijayani Sahu
  • Amarjit S. Naura


We have previously shown that PARP-1 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg/kg b.wt. reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially. Olaparib provided strong protection against LPS-mediated secondary kidney injury as reflected by restoration of serum levels of urea, creatinine, and uric acid toward normal. The drug restored the LPS-mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS-induced expression of NF-κB-dependent genes namely TNF-α, IL-1β, and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggest that olaparib has a strong potential to protect against LPS-induced lung injury and associated dysfunctioning of kidney in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.


PARP Olaparib LPS Acute lung injury Acute kidney injury 



The grant support (BT/RLF/Re-entry/36/2012) from Department of Biotechnology, Government of India in the form of Ramalingaswami Fellowship to Dr. Amarjit S. Naura is highly acknowledged. We also acknowledge the Junior Research Fellowship to Bijayani Sahu from University Grant Commission, New Delhi, India.


  1. 1.
    Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349. doi: 10.1056/NEJM200005043421806 CrossRefPubMedGoogle Scholar
  2. 2.
    Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685–1693. doi: 10.1056/NEJMoa050333 CrossRefPubMedGoogle Scholar
  3. 3.
    Dowdy DW, Eid MP, Dennison CR, Mendez-Tellez PA, Herridge MS, Guallar E, Pronovost PJ, Needham DM (2006) Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med 32:1115–1124. doi: 10.1007/s00134-006-0217-3 CrossRefPubMedGoogle Scholar
  4. 4.
    Ware LB (2006) Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med 27:337–349. doi: 10.1055/s-2006-948288 CrossRefPubMedGoogle Scholar
  5. 5.
    Wheeler AP, Bernard GR (2007) Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet 369:1553–1564. doi: 10.1016/S0140-6736(07)60604-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Martinez O, Nin N, Esteban A (2009) Prone position for the treatment of acute respiratory distress syndrome: a review of current literature. Arch Bronconeumol 45:291–296. doi: 10.1016/j.arbres.2008.05.010 CrossRefPubMedGoogle Scholar
  7. 7.
    Chang R, Wang Y, Chang J, Wen L, Jiang Z, Yang T, Yu K (2014) LPS preconditioning ameliorates intestinal injury in a rat model of hemorrhagic shock. Inflamm Res 63:675–682. doi: 10.1007/s00011-014-0740-6 CrossRefPubMedGoogle Scholar
  8. 8.
    Kitamura Y, Hashimoto S, Mizuta N, Kobayashi A, Kooguchi K, Fujiwara I, Nakajima H (2001) Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am J Respir Crit Care Med 163:762–769. doi: 10.1164/ajrccm.163.3.2003065 CrossRefPubMedGoogle Scholar
  9. 9.
    Matute-Bello G, Winn RK, Martin TR, Liles WC (2004) Sustained lipopolysaccharide-induced lung inflammation in mice is attenuated by functional deficiency of the Fas/Fas ligand system. Clin Diagn Lab Immunol 11:358–361PubMedCentralPubMedGoogle Scholar
  10. 10.
    Rojas M, Woods CR, Mora AL, Xu J, Brigham KL (2005) Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am J Physiol Lung Cell Mol Physiol 288:L333–L341. doi: 10.1152/ajplung.00334.2004 CrossRefPubMedGoogle Scholar
  11. 11.
    Matute-Bello G, Frevert CW, Martin TR (2008) Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295:L379–L399. doi: 10.1152/ajplung.00010.2008 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Singbartl K, Bishop JV, Wen X, Murugan R, Chandra S, Filippi MD, Kellum JA (2011) Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia. Kidney Int 80:633–644. doi: 10.1038/ki.2011.201 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Vieira JM Jr, Castro I, Curvello-Neto A, Demarzo S, Caruso P, Pastore L Jr, Imanishe MH, Abdulkader RC, Deheinzelin D (2007) Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 35:184–191. doi: 10.1097/01.CCM.0000249828.81705.65 CrossRefPubMedGoogle Scholar
  14. 14.
    Liu KD, Matthay MA (2008) Advances in critical care for the nephrologist: acute lung injury/ARDS. Clin J Am Soc Nephrol 3:578–586. doi: 10.2215/CJN.01630407 CrossRefPubMedGoogle Scholar
  15. 15.
    Sodhi RK, Singh N, Jaggi AS (2010) Poly (ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. Vasc Pharmacol 53:77–87. doi: 10.1016/j.vph.2010.06.003 CrossRefGoogle Scholar
  16. 16.
    de la Lastra CA, Villegas I, Sanchez-Fidalgo S (2007) Poly (ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr Pharm Des 13:933–962CrossRefPubMedGoogle Scholar
  17. 17.
    Virag L, Szabo C (2002) The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429CrossRefPubMedGoogle Scholar
  18. 18.
    Pacher P, Szabo C (2008) Role of the peroxynitrite-poly (ADP-ribose) polymerase pathway in human disease. Am J Pathol 173:2–13. doi: 10.2353/ajpath.2008.080019 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Ame JC, Spenlehauer C, de Murcia G (2004) The PARP superfamily. Bioessays 26:882–893. doi: 10.1002/bies.20085 CrossRefPubMedGoogle Scholar
  20. 20.
    Herceg Z, Wang ZQ (2001) Functions of poly (ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110CrossRefPubMedGoogle Scholar
  21. 21.
    Dantzer F, Ame JC, Schreiber V, Nakamura J, Menissier-de Murcia J, de Murcia G (2006) Poly (ADP-ribose) polymerase-1 activation during DNA damage and repair. Methods Enzymol 409:493–510. doi: 10.1016/S0076-6879(05)09029-4 CrossRefPubMedGoogle Scholar
  22. 22.
    Kraus WL, Lis JT (2003) PARP goes transcription. Cell 113:677–683CrossRefPubMedGoogle Scholar
  23. 23.
    Kraus WL (2008) Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol 20:294–302. doi: 10.1016/ PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    D’Amours D, Desnoyers S, D’Silva I, Poirier GG (1999) Poly (ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342(Pt 2):249–268PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Shall S, de Murcia G (2000) Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model? Mutat Res 460:1–15CrossRefPubMedGoogle Scholar
  26. 26.
    Hassa PO, Hottiger MO (1999) A role of poly (ADP-ribose) polymerase in NF-kappaB transcriptional activation. Biol Chem 380:953–959. doi: 10.1515/BC.1999.118 CrossRefPubMedGoogle Scholar
  27. 27.
    Oliver FJ, Menissier-de Murcia J, Nacci C, Decker P, Andriantsitohaina R, Muller S, de la Rubia G, Stoclet JC, de Murcia G (1999) Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 18:4446–4454. doi: 10.1093/emboj/18.16.4446 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Zerfaoui M, Errami Y, Naura AS, Suzuki Y, Kim H, Ju J, Liu T, Hans CP, Kim JG, Abd Elmageed ZY, Koochekpour S, Catling A, Boulares AH (2010) Poly (ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation. J Immunol 185:1894–1902. doi: 10.4049/jimmunol.1000646 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Naura AS, Datta R, Hans CP, Zerfaoui M, Rezk BM, Errami Y, Oumouna M, Matrougui K, Boulares AH (2009) Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia. Eur Respir J 33:252–262. doi: 10.1183/09031936.00089008 CrossRefPubMedGoogle Scholar
  30. 30.
    Zerfaoui M, Suzuki Y, Naura AS, Hans CP, Nichols C, Boulares AH (2008) Nuclear translocation of p65 NF-kappaB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: differential requirement for PARP-1 expression and interaction. Cell Signal 20:186–194. doi: 10.1016/j.cellsig.2007.10.007 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Liaudet L, Pacher P, Mabley JG, Virag L, Soriano FG, Hasko G, Szabo C (2002) Activation of poly (ADP-Ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation. Am J Respir Crit Care Med 165:372–377. doi: 10.1164/ajrccm.165.3.2106050 CrossRefPubMedGoogle Scholar
  32. 32.
    Murakami K, Enkhbaatar P, Shimoda K, Cox RA, Burke AS, Hawkins HK, Traber LD, Schmalstieg FC, Salzman AL, Mabley JG, Komjati K, Pacher P, Zsengeller Z, Szabo C, Traber DL (2004) Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock 21:126–133. doi: 10.1097/01.shk.0000108397.56565.4a CrossRefPubMedGoogle Scholar
  33. 33.
    Vaschetto R, Kuiper JW, Chiang SR, Haitsma JJ, Juco JW, Uhlig S, Plotz FB, Della Corte F, Zhang H, Slutsky AS (2008) Inhibition of poly (adenosine diphosphate-ribose) polymerase attenuates ventilator-induced lung injury. Anesthesiology 108:261–268. doi: 10.1097/01.anes.0000299434.86640.15 CrossRefPubMedGoogle Scholar
  34. 34.
    Lord CJ, Ashworth A (2008) Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 8:363–369. doi: 10.1016/j.coph.2008.06.016 CrossRefPubMedGoogle Scholar
  35. 35.
    Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA (2010) Poly (ADP-Ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin Cancer Res 16:4702–4710. doi: 10.1158/1078-0432.CCR-10-0939 PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Ihnen M, zu Eulenburg C, Kolarova T, Qi JW, Manivong K, Chalukya M, Dering J, Anderson L, Ginther C, Meuter A, Winterhoff B, Jones S, Velculescu VE, Venkatesan N, Rong HM, Dandekar S, Udar N, Janicke F, Los G, Slamon DJ, Konecny GE (2013) Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer. Mol Cancer Ther 12:1002–1015. doi: 10.1158/1535-7163.MCT-12-0813 PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Zhang J (2014) Poly (ADP-ribose) polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer. Asian J Androl 16:401–406. doi: 10.4103/1008-682X.123684 PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134. doi: 10.1056/NEJMoa0900212 CrossRefPubMedGoogle Scholar
  39. 39.
    Dean E, Middleton MR, Pwint T, Swaisland H, Carmichael J, Goodege-Kunwar P, Ranson M (2012) Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer 106:468–474. doi: 10.1038/bjc.2011.555 PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Si MK, Mitaka C, Tulafu M, Abe S, Kitagawa M, Ikeda S, Eishi Y, Kurata S, Tomita M (2013) Inhibition of poly (adenosine diphosphate-ribose) polymerase attenuates lung-kidney crosstalk induced by intratracheal lipopolysaccharide instillation in rats. Respir Res 14:126. doi: 10.1186/1465-9921-14-126 CrossRefPubMedGoogle Scholar
  41. 41.
    Zerfaoui M, Naura AS, Errami Y, Hans CP, Rezk BM, Park J, Elsegeiny W, Kim H, Lord K, Kim JG, Boulares AH (2009) Effects of PARP-1 deficiency on airway inflammatory cell recruitment in response to LPS or TNF: differential effects on CXCR2 ligands and duffy antigen receptor for chemokines. J Leukoc Biol 86:1385–1392. doi: 10.1189/jlb.0309183 PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Ghonim MA, Naura AS, Rodriguez P, Al Khami A, Hernandez C, Mansy MS, Ochoa A, Boulares H (2013) Olaparib, a PARP inhibitor approved for human testing, prevents allergen-induced airway inflammation and hyper responsiveness in a mouse model of asthma and reduces proliferation of human CD3/C28-stimulated CD4+ T cells. FASEB J 27:1107.1Google Scholar
  43. 43.
    Kim H, Naura AS, Errami Y, Ju J, Boulares AH (2011) Cordycepin blocks lung injury-associated inflammation and promotes BRCA1-deficient breast cancer cell killing by effectively inhibiting PARP. Mol Med 17:893–900. doi: 10.2119/molmed.2011.00032 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Naura AS, Kalla NR, Sharma RP, Sharma R (2007) Anticarcinogenic effects of hexaamminecobalt (III) chloride in mice initiated with diethylnitrosamine. Biol Trace Elem Res 119:147–165. doi: 10.1007/s12011-007-0051-7 CrossRefPubMedGoogle Scholar
  45. 45.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  46. 46.
    Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310CrossRefPubMedGoogle Scholar
  47. 47.
    Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77CrossRefPubMedGoogle Scholar
  48. 48.
    Kastl L, Sauer SW, Ruppert T, Beissbarth T, Becker MS, Suss D, Krammer PH, Gulow K (2014) TNF-alpha mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-kappaB activation in liver cells. FEBS Lett 588:175–183. doi: 10.1016/j.febslet.2013.11.033 CrossRefPubMedGoogle Scholar
  49. 49.
    Wang LH, Li Y, Yang SN, Wang FY, Hou Y, Cui W, Chen K, Cao Q, Wang S, Zhang TY, Wang ZZ, Xiao W, Yang JY, Wu CF (2014) Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-kappaB and MAPK/HO-1 signalling. Br J Cancer 110:341–352. doi: 10.1038/bjc.2013.752 PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Chian CF, Chiang CH, Chuang CH, Liu SL (2014) Inhibitor of nuclear factor-kappaB, SN50, attenuates lipopolysaccharide-induced lung injury in an isolated and perfused rat lung model. Transl Res 163:211–220. doi: 10.1016/j.trsl.2013.10.002 CrossRefPubMedGoogle Scholar
  51. 51.
    Pan H, Zhang Y, Luo Z, Li P, Liu L, Wang C, Wang H, Li H, Ma Y (2014) Autophagy mediates avian influenza H5N1 pseudotyped particle-induced lung inflammation through NF-kappaB and p38 MAPK signaling pathways. Am J Physiol Lung Cell Mol Physiol 306:L183–L195. doi: 10.1152/ajplung.00147.2013 CrossRefPubMedGoogle Scholar
  52. 52.
    Cross LJ, Matthay MA (2011) Biomarkers in acute lung injury: insights into the pathogenesis of acute lung injury. Crit Care Clin 27:355–377. doi: 10.1016/j.ccc.2010.12.005 PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Hoth JJ, Wells JD, Hiltbold EM, McCall CE, Yoza BK (2011) Mechanism of neutrophil recruitment to the lung after pulmonary contusion. Shock 35:604–609. doi: 10.1097/SHK.0b013e3182144a50 PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Xiang M, Yin L, Li Y, Xiao G, Vodovotz Y, Billiar TR, Wilson MA, Fan J (2011) Hemorrhagic shock activates lung endothelial reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase via neutrophil NADPH oxidase. Am J Respir Cell Mol Biol 44:333–340. doi: 10.1165/rcmb.2009-0408OC PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Le Gars M, Descamps D, Roussel D, Saussereau E, Guillot L, Ruffin M, Tabary O, Hong SS, Boulanger P, Paulais M, Malleret L, Belaaouaj A, Edelman A, Huerre M, Chignard M, Sallenave JM (2013) Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo. Am J Respir Crit Care Med 187:170–179. doi: 10.1164/rccm.201205-0875OC CrossRefPubMedGoogle Scholar
  56. 56.
    Haitsma JJ, Lachmann B, Papadakos PJ (2009) Additives in intravenous anesthesia modulate pulmonary inflammation in a model of LPS-induced respiratory distress. Acta Anaesthesiol Scand 53:176–182. doi: 10.1111/j.1399-6576.2008.01844.x CrossRefPubMedGoogle Scholar
  57. 57.
    Wu CL, Lin LY, Yang JS, Chan MC, Hsueh CM (2009) Attenuation of lipopolysaccharide-induced acute lung injury by treatment with IL-10. Respirology 14:511–521. doi: 10.1111/j.1440-1843.2009.01516.x CrossRefPubMedGoogle Scholar
  58. 58.
    Vaschetto R, Kuiper JW, Musters RJ, Eringa EC, Della Corte F, Murthy K, Groeneveld AB, Plotz FB (2010) Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway. Crit Care 14:R45. doi: 10.1186/cc8932 PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Reiss LK, Uhlig U, Uhlig S (2012) Models and mechanisms of acute lung injury caused by direct insults. Eur J Cell Biol 91:590–601. doi: 10.1016/j.ejcb.2011.11.004 CrossRefPubMedGoogle Scholar
  60. 60.
    van Helden HP, Kuijpers WC, Steenvoorden D, Go C, Bruijnzeel PL, van Eijk M, Haagsman HP (1997) Intratracheal aerosolization of endotoxin (LPS) in the rat: a comprehensive animal model to study adult (acute) respiratory distress syndrome. Exp Lung Res 23:297–316CrossRefPubMedGoogle Scholar
  61. 61.
    Zhao YY, Gao XP, Zhao YD, Mirza MK, Frey RS, Kalinichenko VV, Wang IC, Costa RH, Malik AB (2006) Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury. J Clin Invest 116:2333–2343. doi: 10.1172/JCI27154 PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Huang Z, Zhao C, Chen Y, Cowell JA, Wei G, Kultti A, Huang L, Thompson CB, Rosengren S, Frost GI, Shepard HM (2014) Recombinant human hyaluronidase PH20 does not stimulate an acute inflammatory response and inhibits lipopolysaccharide-induced neutrophil recruitment in the air pouch model of inflammation. J Immunol 192:5285–5295. doi: 10.4049/jimmunol.1303060 CrossRefPubMedGoogle Scholar
  63. 63.
    Yaxin W, Shanglong Y, Huaqing S, Hong L, Shiying Y, Xiangdong C, Ruidong L, Xiaoying W, Lina G, Yan W (2014) Resolvin D1 attenuates lipopolysaccharide induced acute lung injury through CXCL-12/CXCR4 pathway. J Surg Res 188:213–221. doi: 10.1016/j.jss.2013.11.1107 CrossRefPubMedGoogle Scholar
  64. 64.
    Naura AS, Zerfaoui M, Kim H, Abd Elmageed ZY, Rodriguez PC, Hans CP, Ju J, Errami Y, Park J, Ochoa AC, Boulares AH (2010) Requirement for inducible nitric oxide synthase in chronic allergen exposure-induced pulmonary fibrosis but not inflammation. J Immunol 185:3076–3085. doi: 10.4049/jimmunol.0904214 PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Datta R, Naura AS, Zerfaoui M, Errami Y, Oumouna M, Kim H, Ju J, Ronchi VP, Haas AL, Boulares AH (2011) PARP-1 deficiency blocks IL-5 expression through calpain-dependent degradation of STAT-6 in a murine asthma model. Allergy 66:853–861. doi: 10.1111/j.1398-9995.2011.02549.x PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Naura AS, Hans CP, Zerfaoui M, You D, Cormier SA, Oumouna M, Boulares AH (2008) Post-allergen challenge inhibition of poly (ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation. Clin Exp Allergy 38:839–846. doi: 10.1111/j.1365-2222.2008.02943.x PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Kiefmann R, Heckel K, Doerger M, Schenkat S, Kupatt C, Stoeckelhuber M, Wesierska-Gadek J, Goetz AE (2004) Role of PARP on iNOS pathway during endotoxin-induced acute lung injury. Intensive Care Med 30:1421–1431. doi: 10.1007/s00134-004-2301-x CrossRefPubMedGoogle Scholar
  68. 68.
    Goldfarb RD, Marton A, Szabo E, Virag L, Salzman AL, Glock D, Akhter I, McCarthy R, Parrillo JE, Szabo C (2002) Protective effect of a novel, potent inhibitor of poly (adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. Crit Care Med 30:974–980CrossRefPubMedGoogle Scholar
  69. 69.
    Tasatargil A, Aksoy NH, Dalaklioglu S, Sadan G (2008) Poly (ADP-ribose) polymerase as a potential target for the treatment of acute renal injury caused by lipopolysaccharide. Ren Fail 30:115–120. doi: 10.1080/08860220701742195 CrossRefPubMedGoogle Scholar
  70. 70.
    Szabo C, Cuzzocrea S, Zingarelli B, O’Connor M, Salzman AL (1997) Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite. J Clin Invest 100:723–735. doi: 10.1172/JCI119585 PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N (2014) Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-Acetylcysteine. COPD. doi: 10.3109/15412555.2014.898040 PubMedCentralPubMedGoogle Scholar
  72. 72.
    Toygar M, Aydin I, Agilli M, Aydin F, Oztosun M, Gul H, Macit E, Karslioglu Y, Topal T, Uysal B, Honca M (2014) The relation between oxidative stress, inflammation, and neopterin in the paraquat-induced lung toxicity. Hum Exp Toxicol. doi: 10.1177/0960327114533808 PubMedGoogle Scholar
  73. 73.
    Jagtap P, Szabo C (2005) Poly (ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421–440. doi: 10.1038/nrd1718 CrossRefPubMedGoogle Scholar
  74. 74.
    Virag L, Salzman AL, Szabo C (1998) Poly (ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death. J Immunol 161:3753–3759PubMedGoogle Scholar
  75. 75.
    Szabo C, Dawson VL (1998) Role of poly (ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–298CrossRefPubMedGoogle Scholar
  76. 76.
    Peralta-Leal A, Rodriguez-Vargas JM, Aguilar-Quesada R, Rodriguez MI, Linares JL, de Almodovar MR, Oliver FJ (2009) PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med 47:13–26. doi: 10.1016/j.freeradbiomed.2009.04.008 CrossRefPubMedGoogle Scholar
  77. 77.
    Atsuta J, Sterbinsky SA, Plitt J, Schwiebert LM, Bochner BS, Schleimer RP (1997) Phenotyping and cytokine regulation of the BEAS-2B human bronchial epithelial cell: demonstration of inducible expression of the adhesion molecules VCAM-1 and ICAM-1. Am J Respir Cell Mol Biol 17:571–582. doi: 10.1165/ajrcmb.17.5.2685 CrossRefPubMedGoogle Scholar
  78. 78.
    Szabo C, Wong H, Bauer P, Kirsten E, Oconnor M, Zingarelli B, Mendeleyev J, Hasko G, Vizi E, Salzman A, Kun E (1997) Regulation of components of the inflammatory response by 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly (ADP-ribose) synthetase and pleiotropic modifier of cellular signal pathways. Int J Oncol 10:1093–1101PubMedGoogle Scholar
  79. 79.
    Sheridan BC, McIntyre RC, Meldrum DR, Fullerton DA (1997) Pentoxifylline treatment attenuates pulmonary vasomotor dysfunction in acute lung injury. J Surg Res 71:150–154. doi: 10.1006/jsre.1997.5144 CrossRefPubMedGoogle Scholar
  80. 80.
    Witkamp R, Monshouwer M (2000) Signal transduction in inflammatory processes, current and future therapeutic targets: a mini review. Vet Q 22:11–16. doi: 10.1080/01652176.2000.9695016 CrossRefPubMedGoogle Scholar
  81. 81.
    Glosli H, Tronstad KJ, Wergedal H, Muller F, Svardal A, Aukrust P, Berge RK, Prydz H (2002) Human TNF-alpha in transgenic mice induces differential changes in redox status and glutathione-regulating enzymes. FASEB J 16:1450–1452. doi: 10.1096/fj.01-0948fje PubMedGoogle Scholar
  82. 82.
    Liu KD, Thompson BT, Ancukiewicz M, Steingrub JS, Douglas IS, Matthay MA, Wright P, Peterson MW, Rock P, Hyzy RC, Anzueto A, Truwit JD, National Institutes of Health National Heart L and Blood Institute Acute Respiratory Distress Syndrome Network (2011) Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med 39:2665–2671. doi: 10.1097/CCM.0b013e318228234b PubMedCentralPubMedGoogle Scholar
  83. 83.
    Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O’Connor MJ, Smith GC, Martin NM (2008) 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly (ADP-ribose) polymerase-1. J Med Chem 51:6581–6591. doi: 10.1021/jm8001263 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kunal Kapoor
    • 1
  • Esha Singla
    • 1
  • Bijayani Sahu
    • 1
    • 2
  • Amarjit S. Naura
    • 1
  1. 1.Department of BiochemistryPanjab UniversityChandigarhIndia
  2. 2.Department of ZoologyPanjab UniversityChandigarhIndia

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