Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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The Role of Poly(ADP-ribose) Polymerase-1 in Ventilator-Induced Lung Injury

기계환기로 인한 급성 폐손상에서 poly(ADP-ribose) polymerase-1의 역할

  • Kim, Je-Hyeong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Yoon, Dae Wui (Institute of Human Genomic Study, Ansan Hospital, Korea University Medical Center) ;
  • Hur, Gyu Young (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Jung, Ki Hwan (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Sung Yong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Sang Yeub (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Shin, Chol (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Shim, Jae Jeong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • In, Kwang Ho (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Yoo, Se Hwa (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kang, Kyung Ho (Department of Internal Medicine, College of Medicine, Korea University)
  • 김제형 (고려대학교 의과대학 내과학교실) ;
  • 윤대위 (고려대학교의료원 안산병원 인간유전체연구소) ;
  • 허규영 (고려대학교 의과대학 내과학교실) ;
  • 정기환 (고려대학교 의과대학 내과학교실) ;
  • 이승룡 (고려대학교 의과대학 내과학교실) ;
  • 이상엽 (고려대학교 의과대학 내과학교실) ;
  • 신철 (고려대학교 의과대학 내과학교실) ;
  • 심재정 (고려대학교 의과대학 내과학교실) ;
  • 인광호 (고려대학교 의과대학 내과학교실) ;
  • 유세화 (고려대학교 의과대학 내과학교실) ;
  • 강경호 (고려대학교 의과대학 내과학교실)
  • Received : 2006.01.23
  • Accepted : 2006.04.24
  • Published : 2006.04.30
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Abstract

Background : Reactive oxygen species (ROS) take center stage as executers in ventilator-induced lung injury (VILI). The protein with DNA-damage scanning activity, poly (ADP-ribose) polymerase-1 (PARP1), signals DNA rupture and participates in base-excision repair. Paradoxically,overactivation of PARP1 in response to massive genotoxic injury such as ROS can induce cell death through ${\beta}$ -nicotinamide adenine dinucleotide ($NAD^+$) depletion, resulting in inflammation. The purpose of this study is to investigate the role of PARP1 and the effect of its inhibitor in VILI. Methods : Forty-eight male C57BL/6 mice were divided into sham, lung protective ventilation(LPV), VILI, and PARP1 inhibitor (PJ34)+VILI (PJ34+VILI) groups. Mechanical ventilator setting for the LPV group was $PIP\;15cmH_2O$ + $PEEP\;3cmH_2O$ + RR 90/min + 2 hours. The VILI and PJ34+VILI groups were ventilated on a setting of $PIP\;40cmH_2O$ + $PEEP\;0cmH_2O$ + RR 90/min + 2 hours. As a PARP1 inhibitor for the PJ34+VILI group, 20 mg/Kg of PJ34 was treated intraperitoneally 2 hours before mechanical ventilation. Wet-to-dry weight ratio and acute lung injury (ALI) score were measured to determine the degree of VILI. PARP1 activity was evaluated by using an immunohistochemical method utilizing biotinylated NAD. Myeloperoxidase (MPO) activity and the concentration of inflammatory cytokines such as tumor necrosis factor $(TNF)-{\alpha}$, interleukin $(IL)-1{\beta}$, and IL-6 were measured in bronchoalveolar lavage fluid (BALF). Results : In the PJ34+VILI group, PJ34 pretreatment significantly reduced the degree of lung injury, compared with the VILI group (p<0.05). The number of cells expressing PARP1 activity was significantly increased in the VILI group, but significantly decreased in the PJ34+VILI group (p=0.001). In BALF, MPO activity, $TNF-{\alpha}$, $IL-1{\beta}$, and IL-6 were also significantly lower in the PJ34+VILI group (all, p<0.05). Conclusion : PARP1 overactivation plays a major role in the mechanism of VILI. PARP1 inhibitor prevents VILI, and decreases MPO activity and inflammatory cytokines.

연구배경: 활성산소종은 기계환기로 인한 폐손상 (ventilator-induced lung injury, VILI)에서 주요한 역할을 한다. Poly (ADP-ribose) polymerase-1 (PARP1)은 DNA 손상 감시 기능을 하는 단백질로서, DNA 파열을 신호하고 복구에 관여한다. 그러나 활성산소종에 의한 것과 같은 심한 유전자 손상을 받게 되면, 과활성화되어 ${\beta}$-nicotinamide adenine dinucleotide ($NAD^+$)의 결핍을 통한 세포의 사멸을 초래하여, 염증 반응을 일으킨다. 본 연구에서는 VILI의 기전에 있어서 PARP1의 역할 및 그 억제제의 효과를 고찰하고자 하였다. 방법: 48마리의 수컷 C57BL/6 생쥐를 겉보기 수술군 (Sham군), 폐보호적 환기군(lung protective ventilation group, LPV군), 기계환기기로 인한 폐손상군 (ventilator-induced lung injury group, VILI군) 및 PARP1 억제제인 PJ34 전처치 후 기계환기로 인한 폐손상군 (PJ34+VILI군)으로 나누어 실험하였다. LPV군에 대한 기계환기는 $PIP\;15cmH_2O$ + $PEEP\;3cmH_2O$ + RR 90/min. 조건으로, VILI 및 PJ34+VILI군에 대해서는 $PIP\;40cmH_2O$ + $PEEP\;0cmH_2O$ + RR 90/min.의 조건으로 2시간 동안 시행하였다. PJ34+VILI군에서 PARP1 억제제로는, PJ34 20 mg/Kg을 기계환기 2시간 전에 복강 내로 주사하였다. VILI의 정도는 습건중량비 및 급성폐손상 지수로 측정하였고, PARP1의 활성은 biotinylated NAD를 이용한 면역조직화학적 방법을 이용하였다. 또한 기관지폐포세척액 (bronchoalveolar lavage fluid, BALF) 내에서 myeloperoxidase (MPO) 활성 및 tumor necrosis factor-${\alpha}$ ($TNF-{\alpha}$), interleukin-$1{\beta}$ ($IL-1{\beta}$), IL-6 등의 염증성 시토카인의 농도를 측정하였다. 결과: PJ34+VILI군에서 VILI군과 비교하여, PJ34 전처치로 인하여 폐손상의 정도가 현저히 감소하였다 (p<0.05). 5개의 고배율 시야에서 관찰한 PARP1의 활성을 보이는 세포의 수는 VILI군에서 유의하게 증가하였고, PJ34+VILI군에서 현저히 감소하였다 (p=0.001). BALF 내에서 측정한 MPO 활성 및 $TNF-{\alpha}$, $IL-1{\beta}$, IL-6의 농도 역시 PJ34+VILI군에서 의미 있게 감소하였다 (p<0.05). 결론: VILI의 기전에 있어서 PARP1의 과활성이 주요한 역할을 하고, PARP1 억제제가 MPO 활성 및 염증성 시토카인의 감소와 함께 VILI의 발생을 억제한다.

Keywords

References

  1. International consensus conferences in intensive care medicine: ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999;160:2118-24 https://doi.org/10.1164/ajrccm.160.6.ats16060
  2. Slutsky AS, Tremblay LN. Multiple system organ failure: is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998;157:1721-5 https://doi.org/10.1164/ajrccm.157.6.9709092
  3. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-8 https://doi.org/10.1056/NEJM200005043421801
  4. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-54 https://doi.org/10.1056/NEJM199802053380602
  5. Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians 1998;110:482-8
  6. Uhlig S, Uhlig U. Pharmacological interventions in ventilator-induced lung injury. Trends Pharmacol Sci 2004;25:592-600 https://doi.org/10.1016/j.tips.2004.09.002
  7. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays 2004;26:882-93 https://doi.org/10.1002/bies.20085
  8. Bouchard VJ, Rouleau M, Poirier GG. PARP-1, a determinant of cell survival in response to DNA damage. Exp Hematol 2003;31:446-54 https://doi.org/10.1016/S0301-472X(03)00083-3
  9. Huber A, Bai P, de Murcia JM, de Murcia G. PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair 2004;3:1103-8 https://doi.org/10.1016/j.dnarep.2004.06.002
  10. Nguewa PA, Fuertes MA, Valladares B, Alonso C, Perez JM. Poly(ADP-ribose) polymerases: homology, structural domains and functions: novel therapeutical applications. Prog Biophys Mol Biol 2005;88:143-72 https://doi.org/10.1016/j.pbiomolbio.2004.01.001
  11. Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002;54:375-429 https://doi.org/10.1124/pr.54.3.375
  12. D'Amours D, Desnoyers S, D'Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 1999;342:249-68 https://doi.org/10.1042/0264-6021:3420249
  13. Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001;477:97-110 https://doi.org/10.1016/S0027-5107(01)00111-7
  14. Berger NA. Poly(ADP-ribose) in the cellular response to DNA damage. Radiat Res 1985;101:4-15 https://doi.org/10.2307/3576299
  15. Berger NA, Berger SJ. Metabolic consequences of DNA damage: the role of poly (ADP-ribose) polymerase as mediator of the suicide response. Basic Life Sci 1986;38:357-63 https://doi.org/10.1016/0024-3205(86)90083-4
  16. Berger NA, Whitacre CM, Hashimoto H, Berger SJ, Chatterjee S. NAD and poly(ADP-ribose) regulation of proteins involved in response to cellular stress and DNA damage. Biochimie 1995;77:364-7 https://doi.org/10.1016/0300-9084(96)88147-8
  17. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 1997;3:1089-95 https://doi.org/10.1038/nm1097-1089
  18. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 1999;96:13978-82 https://doi.org/10.1073/pnas.96.24.13978
  19. Heller B, Wang ZQ, Wagner EF, Radons J, Burkle A, Fehsel K, et al. Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells. J Biol Chem 1995;270: 11176-80 https://doi.org/10.1074/jbc.270.19.11176
  20. Szabo C, Zingarelli B, O'Connor M, Salzman AL. DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci U S A 1996;93:1753-8 https://doi.org/10.1073/pnas.93.5.1753
  21. Virag L, Salzman AL, Szabo C. Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death. J Immunol 1998;161: 3753-9
  22. Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 1994;263:687-9 https://doi.org/10.1126/science.8080500
  23. Zingarelli B, O'Connor M, Wong H, Salzman AL, Szabo C. Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. J Immunol 1996;156:350-8
  24. Zingarelli B, Salzman AL, Szabo C. Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 1998;83:85-94 https://doi.org/10.1161/01.RES.83.1.85
  25. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294-323 https://doi.org/10.1164/ajrccm.157.1.9604014
  26. Imanaka H, Shimaoka M, Matsuura N, Nishimura M, Ohta N, Kiyono H. Ventilator-induced lung injury is associated with neutrophil infiltration, macrophage activation, and TGF-beta 1 mRNA upregulation in rat lungs. Anesth Analg 2001;92:428-36 https://doi.org/10.1213/00000539-200102000-00029
  27. Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 2001;7:108-13 https://doi.org/10.1038/83241
  28. Zhang J. Use of biotinylated NAD to label and purify ADP-ribosylated proteins. Methods Enzymol 1997;280: 255-65 https://doi.org/10.1016/S0076-6879(97)80117-6
  29. Liaudet L, Pacher P, Mabley JG, Virag L, Soriano FG, Hasko G, et al. Activation of poly(ADP-Ribose) polymerase- 1 is a central mechanism of lipopolysaccharide- induced acute lung inflammation. Am J Respir Crit Care Med 2002;165:372-7 https://doi.org/10.1164/ajrccm.165.3.2106050
  30. Hirano S. Migratory responses of PMN after intraperitoneal and intratracheal administration of lipopolysaccharide. Am J Physiol 1996;270:L836-45
  31. Tsuno K, Miura K, Takeya M, Kolobow T, Morioka T. Histopathologic pulmonary changes from mechanical ventilation at high peak airway pressures. Am Rev Respir Dis 1991;143:1115-20 https://doi.org/10.1164/ajrccm/143.5_Pt_1.1115
  32. Woo SW, Hedley-Whyte J. Macrophage accumulation and pulmonary edema due to thoracotomy and lung over inflation. J Appl Physiol 1972;33:14-21 https://doi.org/10.1152/jappl.1972.33.1.14
  33. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997;99:944-52 https://doi.org/10.1172/JCI119259
  34. Matsuoka T, Kawano T, Miyasaka K. Role of high- frequency ventilation in surfactant-depleted lung injury as measured by granulocytes. J Appl Physiol 1994;76:539-44 https://doi.org/10.1152/jappl.1994.76.2.539
  35. Sugiura M, McCulloch PR, Wren S, Dawson RH, Froese AB. Ventilator pattern influences neutrophil influx and activation in atelectasis-prone rabbit lung. J Appl Physiol 1994;77:1355-65 https://doi.org/10.1152/jappl.1994.77.3.1355
  36. Takata M, Abe J, Tanaka H, Kitano Y, Doi S, Kohsaka T, et al. Intraalveolar expression of tumor necrosis factor-alpha gene during conventional and high-frequency ventilation. Am J Respir Crit Care Med 1997;156:272-9 https://doi.org/10.1164/ajrccm.156.1.9607072
  37. sOkuyama K. Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Am J Respir Crit Care Med 1994;150:1550-4 https://doi.org/10.1164/ajrccm.150.6.7952613
  38. Zhang H, Downey GP, Suter PM, Slutsky AS, Ranieri VM. Conventional mechanical ventilation is associated with bronchoalveolar lavage-induced activation of polymorphonuclear leukocytes: a possible mechanism to explain the systemic consequences of ventilator- induced lung injury in patients with ARDS. Anesthesiology 2002;97:1426-33 https://doi.org/10.1097/00000542-200212000-00014
  39. Jafari B, Ouyang B, Li LF, Hales CA, Quinn DA. Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like cells. Respirology 2004;9:43-53 https://doi.org/10.1111/j.1440-1843.2003.00527.x
  40. Li LF, Yu L, Quinn DA. Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase. Am J Respir Crit Care Med 2004;169:518-24 https://doi.org/10.1164/rccm.200305-660OC
  41. Rimensberger PC, Fedorko L, Cutz E, Bohn DJ. Attenuation of ventilator-induced acute lung injury in an animal model by inhibition of neutrophil adhesion by leumedins (NPC 15669). Crit Care Med 1998; 26:548-55 https://doi.org/10.1097/00003246-199803000-00030
  42. Ohta N, Shimaoka M, Imanaka H, Nishimura M, Taenaka N, Kiyono H, et al. Glucocorticoid suppresses neutrophil activation in ventilator-induced lung injury. Crit Care Med 2001;29:1012-6 https://doi.org/10.1097/00003246-200105000-00027
  43. Chavolla-Calderon M, Bayer MK, Fontan JJ. Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation. J Clin Invest 2003;111:973-80 https://doi.org/10.1172/JCI200317458
  44. Althaus FR, Kleczkowska HE, Malanga M, Muntener CR, Pleschke JM, Ebner M, et al. Poly ADP-ribosylation: a DNA break signal mechanism. Mol Cell Biochem 1999;193:5-11 https://doi.org/10.1023/A:1006975002262
  45. Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, et al. Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis: caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 1999;274:22932-40 https://doi.org/10.1074/jbc.274.33.22932
  46. Boulares AH, Zoltoski AJ, Yakovlev A, Xu M, Smulson ME. Roles of DNA fragmentation factor and poly(ADP-ribose) polymerase in an amplification phase of tumor necrosis factor-induced apoptosis. J Biol Chem 2001;276:38185-92
  47. Ding R, Pommier Y, Kang VH, Smulson M. Depletion of poly(ADP-ribose) polymerase by antisense RNA expression results in a delay in DNA strand break rejoining. J Biol Chem 1992;267:12804-12
  48. Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 2005;4:421-40 https://doi.org/10.1038/nrd1718
  49. Szabo C, Lim LH, Cuzzocrea S, Getting SJ, Zingarelli B, Flower RJ, et al. Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts antiinflammatory effects. J Exp Med 1997;186: 1041-9 https://doi.org/10.1084/jem.186.7.1041
  50. Zingarelli B, Hake PW, O'Connor M, Denenberg A, Wong HR, Kong S, et al. Differential regulation of activator protein-1 and heat shock factor-1 in myocardial ischemia and reperfusion injury: role of poly (ADP-ribose) polymerase-1. Am J Physiol Heart Circ Physiol 2004;286:H1408-15 https://doi.org/10.1152/ajpheart.00953.2003
  51. Chapman KE, Sinclair SE, Zhuang D, Hassid A, Desai LP, Waters CM. Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 2005;289:L834-41 https://doi.org/10.1152/ajplung.00069.2005
  52. Abdelkarim GE, Gertz K, Harms C, Katchanov J, Dirnagl U, Szabo C, et al. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med 2001;7:255-60