Journal List > Tuberc Respir Dis > v.60(4) > 1000940

Kim, Yoon, Hur, Jung, Lee, Lee, Shin, Shim, In, Yoo, and Kang: The Role of Poly(ADP-ribose) Polymerase-1 in Ventilator-Induced Lung Injury

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)+VILI (PJ34+VILI) 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 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)-α, interleukin (IL)-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, IL-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. PARP1 inhibitor prevents VILI, and decreases MPO activity and inflammatory cytokines.

Figures and Tables

Figure 1
In the setting of 40 cmH2O of peak inspiratory pressure, 0 cmH2O of positive end-expiratory pressure, and 90 per minute of respiration rate, the degree of ventilator-induced lung injury increased with the lapse of time. The findings of severe acute lung injury such as alveolar congestion, hemorrhage, infiltration of inflammatory cells and thickening of alveolar wall were most prominent at about 120 minutes after mechanical ventilation (hematoxylin and eosin stain, ×100).
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Figure 2
Histopathologic examination shows high levels of intra-alveolar exudates, inflammatory infiltration, hemorrhage, and interstitial edema in the VILI group. In the LPV group, significant acute lung injury was absent and only mild inflammatory cellular infiltration was observed. The PJ34+VILI group shows a moderately higher level of inflammatory cell infiltration and congestion than the LPV group, while the overall degree of lung injury was significantly lower than the VILI group (hematoxylin eosin stain).
Sham: sham group, LPV: lung protective ventilation group, VILI: ventilator-induced lung injury group, PJ34+VILI: poly(ADP-ribose) polymerase-1 inhibitor (PJ34)+VILI group
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Figure 3
Acute lung injury score (A) and wet-to-dry weight ratio (B) were significantly different among the groups (p=0.000 and p=0.001 by Kruskal-Wallis test, respectively) and higher in the VILI group than the other groups (*p<0.05, compared with other groups).
Sham: sham group, LPV: lung protective ventilation group, VILI: ventilator-induced lung injury group, PJ34+VILI: poly(ADP-ribose) polymerase-1 inhibitor (PJ34)+VILI group
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Figure 4
In immunohistochemical method utilizing biotinylated NAD, the cells with poly(ADP-ribose) polymerase-1 (PARP1) activity were stained as dark black color. In the VILI group, the number of cells with PARP1 activity enormously increased compared with the sham or LPV groups. After PARP1 inhibitor, PJ34, pretreatment, the PARP1 activity positive cells significantly decreased in the PJ34+VILI group.
Sham: sham group, LPV: lung protective ventilation group, VILI: ventilator-induced lung injury group, PJ34+VILI: poly(ADP-ribose) polymerase-1 inhibitor (PJ34)+VILI group
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Figure 5
The number of cells with PARP1 activity in 5 high power fields (HPFs, ×400) (A) and myeloperoxidase (MPO) activity in bronchoalveolar lavage fluid (BALF) (B) were significantly different among the groups (p=0.002 and p=0.001 by Kruskal-Wallis test, respectively) and higher in the VILI group than the other groups (*p<0.05, compared with other groups). MPO activity of PJ34+VILI group was significantly higher than Sham and LPV group (p<0.05)
Sham: sham group, LPV: lung protective ventilation group, VILI: ventilator-induced lung injury group, PJ34+VILI: poly(ADP-ribose) polymerase-1 inhibitor (PJ34)+VILI group
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Figure 6
The concentration of tumor necrosis factor (TNF)-α (A), interleukin (IL)-1β (B), and IL-6 (C) in bronchoalveolar lavage fluid (BALF) were significantly higher in the VILI group than the other groups (*p<0.05, compared with other groups).
ELISA: enzyme-linked immuno-sorbent assay, ND: not detected, Sham: sham group, LPV: lung protective ventilation group, VILI: ventilator-induced lung injury group, PJ34+VILI: poly(ADP-ribose) polymerase-1 inhibitor (PJ34)+VILI group
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Figure 7
Poly(ADP-ribose) polymerase-1 (PARP1) activity showed significant relationship with degree of acute lung injury (ALI) and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) (r=Spearman's rho, *p<0.05 and **p<0.01).
HPF: high power field, TNF-α: tumor necrosis factor-α, IL-1β: interleukin-1β, IL-6: interleukin-6
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