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Pentoxifylline Rescue Preserves Lung Function in Isolated Canine Lungs Injured With Phorbol Myristate Acetate^*

^* From the Department of Pediatrics (Dr. Creamer), Tripler Army Medical Center, Honolulu, HI; and the Vascular Biology Center (Drs. McCloud, Fisher, and Ehrhart), Medical College of Georgia, Augusta, GA.

Correspondence to: Kevin M. Creamer, MD, Department of Pediatrics, MCHK-PE, 1 Jarrett White Rd, Tripler AMC, HI 96859-5000; e-mail: KCLUVSCS{at}AOL.com

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 neutrophil counts. Pulmonary vascular resistance (PVR) and capillary filtration coefficient (Kf) were calculated, and the ratio of a normalized maximal enzymatic 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 µg/mL of perfusate). The pentoxifylline-protected lobes (n = 8) were treated with pentoxifylline (1 mg/mL of perfusate) 10 min after injury with PMA. All 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 injured 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/cm H₂O and 9.6 ± 1.1 to 9.9 ± 0.85 mL/cm H₂O in the control and protected lobes, respectively. Both groups receiving PMA had similar drops in WBC and neutrophil counts, but the pentoxifylline-protected lobes had preservation 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 < 25% in the protected group but more than tripled in the injured group. Amax/Km dropped from 559 ± 36 to 441 ± 33 mL/min (p < 0.05) in the injured lobes vs 507 ± 14 to 490 ± 17 mL/min and 609 ± 34 to 616 ± 37 mL/min in the control and pentoxifylline-protected lobes, respectively.

Conclusions: The use of pentoxifylline as a rescue agent prevented the PMA-induced deterioration of lung compliance, vascular integrity, and endothelial metabolic function in this acute lung injury model, despite significant pulmonary neutrophil sequestration.

Key Words: acute lung injury • pentoxifylline • phorbol myristate acetate • pulmonary function

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