Pentoxifylline rescue preserves lung function in isolated canine lungs injured with phorbol myristate acetate

Objective: We hypothesized that pentoxifylline, administered after phorbol myristate acetate (PMA), would diminish the severity of lung injury. Setting: Animal research laboratory. Design: Comparative study. Subjects: Mongrel dogs (n = 33). Interventions: Baseline measurements were obtained from the isolated blood- perfused dog lung lobes after 1 h of stable perfusion and ventilation. Four different measures of lung compliance were obtained along with WBC and neu trophil counts. Pulmonary vascular resistance (PVR) and capillary filtratio n coefficient (Kf) were calculated and the ratio of a normalized maximal en zymatic conversion rate to the Michaelis-Menten constant (Amax/Km) was used to assess perfused capillary surface area. The control lobes (n = 8) were ventilated and perfused for an additional 40 min while the injured lobes (n = 17) received PMA (0.1 mug/mL of perfusate), The pentoxrifylline-protecte d lobes (n = 8) were treated with pentoxifylline (1 mg/mL of perfusate) 10 min after injury with PMA. Ah measurements were then repeated. Measurement and main results: The three groups did not differ significantly at baseline. The control lobes remained relatively stable over time. The i njured lobes demonstrated marked deterioration in compliance: 8.79 +/- 0.7 to 5.97 +/- 0.59 mL/cm H2O (p < 0.05) vs 10.1 +/- 1.0 to 8.07 +/- 0.72 mL/c m H2O and 9.6 +/- 1.1 to 9.9 +/- 0.85 mL/cm H2O in the control and protecte d lobes, respectively. Both groups receiving PMA had similar drops in WBC a nd neutrophil counts, but the pentoxifylline-protected lobes had preservati on of all four compliance measures. PVR increased from 37.8 +/- 1.8 to 118. 6 +/- 12.7 cm H2O/L/min (p < 0.05) in the injured lobes vs 35.4 +/- 0.5 to 36.3 +/- 2.8 cm H2O/L/min and 40.4 +/- 0.04 to 46.7 +/- 2.8 cm H2O/L/min (p < 0.05) in the control and protected lobes, respectively. Kf increased < 2 5% in the protected group but more than tripled in the injured group. Amaw/ Km dropped from 559 +/- 36 to 441 +/- 33 mL/min (p < 0.05) in the injured l obes vs 507 +/- 14 to 490 +/- 17 mL/min and 490 +/- 34 to 616 +/- 37 mL/min in the control and pentoxifylline-protected lobes, respectively. Conclusio ns: The use of pentoxifylline as a rescue agent prevented the PMA-induced d eterioration of lung compliance, vascular integrity, and endothelial metabo lic function in this acute lung injury model, despite significant pulmonary neutrophil sequestration.