Inhibition of poly(adenosine diphosphate-ribose) polymerase attenuates ventilator-induced lung injury.
BACKGROUND
Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury.


METHODS
Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34.


RESULTS
The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney.


CONCLUSIONS
The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.
Vaschetto
Rosanna
R
The Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Kuiper
Jan W
JW
Chiang
Shyh Ren
SR
Haitsma
Jack J
JJ
Juco
Jonathan W
JW
Uhlig
Stefan
S
Plötz
Frans B
FB
Della Corte
Francesco
F
Zhang
Haibo
H
Slutsky
Arthur S
AS
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D008168:Lung / Q000503:physiopathology*; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011175:Positive-Pressure Respiration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D013925:Thromboplastin / Q000378:metabolism; D013990:Tidal Volume; D014947:Wounds and Injuries / Q000517:prevention & control*
D016207:Cytokines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013925:Thromboplastin