The role of poly(ADP-ribose) polymerase-1 in ventilator-induced lung injury

Je Hyeong Kim, Dae Wui Yoon, Gyu Young Hur, Ki Hwan Jung, Sung Yong Lee, Sang Yeub Lee, Chol Shin, Jae Jeong Shim, Kwang Ho In, Se Hwa Yoo, Kyung Ho Kang

Research output: Contribution to journalArticle

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 β-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)+VELI (PJ34+VHJ) groups. Mechanical ventilator setting for the LPV group was PIP 15 CmH2O + PEEP 3 CmH2O + RR 90/min + 2 hours. The VILI and PJ34+VILI groups were ventilated on a setting of PIP 40 CmH2O + PEEP 0 cmH2O + RR 90/min + 2 hours. As a PARP1 inhibitor for the PJ34+VILI group, 20 mg/Kg of PJ34 was treated intraperitoneaUy 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)-α, interleukin (LL)-1β, 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-α, LL-1β, 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, PARPl inhibitor prevents VILI, and decreases MPO activity and inflammatory cytokines.

Original languageEnglish
Pages (from-to)451-463
Number of pages13
JournalTuberculosis and Respiratory Diseases
Volume60
Issue number4
Publication statusPublished - 2006 Apr 1

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Keywords

  • Acute lung injury
  • Poly (ADP-ribose) polymerase-1
  • Poly (ADP-ribose) polymerase-1 inhibitor
  • Ventilator-induced lung injury

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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