Inflammatory and transcriptional roles of poly (ADP-ribose) polymerase in ventilator-induced lung injury

INTRODUCTION: Poly (ADP-ribose) polymerase (PARP) participates in inflammation by cellular necrosis and the nuclear factor-kappa-B (NF-κB)-dependent transcription. The purpose of this study was to examine the roles of PARP in ventilator-induced lung injury (VILI) in normal mice lung. METHODS: Male C57BL/6 mice were divided into four groups: sham tracheostomized (sham), lung-protective ventilation (LPV), VILI, and VILI with PARP inhibitor PJ34 pretreatment (PJ34+VILI) groups. Mechanical ventilation (MV) settings were peak inspiratory pressure (PIP) 15 cm H(2)O + positive end-expiratory pressure (PEEP) 3 cm H(2)O + 90 breaths per minute for the LPV group and PIP 40 cm H(2)O + PEEP 0 cm H(2)O + 90 breaths per minute for the VILI and PJ34+VILI groups. After 2 hours of MV, acute lung injury (ALI) score, wet-to-dry (W/D) weight ratio, PARP activity, and dynamic compliance (C(D)) were recorded. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO) activity, and nitrite/nitrate (NO(X)) in the bronchoalveolar lavage fluid and NF-κB DNA-binding activity in tissue homogenates were measured. RESULTS: The VILI group showed higher ALI score, W/D weight ratio, MPO activity, NO(X), and concentrations of TNF-α and IL-6 along with lower C(D )than the sham and LPV groups (P < 0.05). In the PJ34+VILI group, PJ34 pretreatment improved all histopathologic ALI, inflammatory profiles, and pulmonary dynamics (P < 0.05). NF-κB activity was increased in the VILI group as compared with the sham and LPV groups (P < 0.05) and was decreased in the PJ34+VILI group as compared with the VILI group (P = 0.009). Changes in all parameters were closely correlated with the PARP activity (P < 0.05). CONCLUSION: Overactivation of PARP plays an important role in the inflammatory and transcriptional pathogenesis of VILI, and PARP inhibition has potentially beneficial effects on the prevention and treatment of VILI.