Inflammatory and transcriptional roles of poly (ADP-ribose) polymerase in ventilator-induced lung injury.
BACKGROUND
Poly (ADP-ribose) polymerase (PARP) participates in inflammation by cellular necrosis and the nuclear factor-kappa-B (NF-kappaB)-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 H2O + positive end-expiratory pressure (PEEP) 3 cm H2O + 90 breaths per minute for the LPV group and PIP 40 cm H2O + PEEP 0 cm H2O + 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 (CD) were recorded. Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), myeloperoxidase (MPO) activity, and nitrite/nitrate (NOX) in the bronchoalveolar lavage fluid and NF-kappaB DNA-binding activity in tissue homogenates were measured.


RESULTS
The VILI group showed higher ALI score, W/D weight ratio, MPO activity, NOX, and concentrations of TNF-alpha and IL-6 along with lower CD 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-kappaB 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).


CONCLUSIONS
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.
Kim
Je Hyeong
JH
Division of Pulmonary, Sleep and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, 516, Gojan 1-dong, Danwon-gu, Ansan 425-707, Republic of Korea.
Suk
Min Hyun
MH
Yoon
Dae Wui
DW
Kim
Hye Young
HY
Jung
Ki Hwan
KH
Kang
Eun Hae
EH
Lee
Sung Yong
SY
Lee
Sang Yeub
SY
Suh
In Bum
IB
Shin
Chol
C
Shim
Jae Jeong
JJ
In
Kwang Ho
KH
Yoo
Se Hwa
SH
Kang
Kyung Ho
KH
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D012121:Respiration, Artificial / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology* / Q000209:etiology / Q000473:pathology
D018836:Inflammation Mediators; D011065:Poly(ADP-ribose) Polymerases