Inhibition of Poly(Adenosine Diphosphate-Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

• Published in: Anesthesiology (Philadelphia) Vol. 108; no. 2; pp. 261 - 268
• Main Authors: VASCHETTO, Rosanna, KUIPER, Jan W, CHIANG, Shyh Ren, HAITSMA, Jack J, JUCO, Jonathan W, UHLIG, Stefan, PLÖTZ, Frans B, CORTE, Francesco Della, HAIBO ZHANG, SLUTSKY, Arthur S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01-02-2008
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid; Cytokines - metabolism; Lung - physiopathology; Male; Medical sciences; Poly(ADP-ribose) Polymerase Inhibitors; Positive-Pressure Respiration; Rats; Rats, Sprague-Dawley; Respiration, Artificial; Thromboplastin - metabolism; Tidal Volume; Wounds and Injuries - prevention & control; Lung disease; Purine nucleoside; Adenosine; Ventilator; Respiratory disease; Ribose; Anesthesia
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/01.anes.0000299434.86640.15

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.
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.
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.
The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.