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

• Published in: Chest Vol. 119; no. 6; pp. 1893 - 1900
• Main Authors: Creamer, Kevin M., McCloud, Laryssa L., Fisher, Lyle E., Ehrhart, Ina C.
• Format: Journal Article
• Language: English
• Published: Northbrook, IL Elsevier Inc 01.06.2001; American College of Chest Physicians
• Subjects: acute lung injury; Animals; Biological and medical sciences; Dogs; Free Radical Scavengers - pharmacology; In Vitro Techniques; Leukocyte Count; Lung - blood supply; Lung - drug effects; Lung - physiology; Lung Compliance - drug effects; Medical sciences; pentoxifylline; Pentoxifylline - pharmacology; Peptidyl-Dipeptidase A - metabolism; phorbol myristate acetate; Platelet Aggregation Inhibitors - pharmacology; Pneumology; pulmonary function; Respiratory system : syndromes and miscellaneous diseases; Tetradecanoylphorbol Acetate - adverse effects; Vascular Resistance - drug effects; Vasodilator Agents - pharmacology; 3H-BPAP; ACE; PEEP; PMA; pulmonary function; acute lung injury; Amax/Km; LLL; PVR; TNF; phorbol myristate acetate; PMN; ANC; pentoxifylline; Kf; ALI; Vt; Fissipedia; Pharmacologic test; Carnivora; Respiratory disease; Bronchodilator; Lung; Compliance(volume pressure); Endothelium; Pentoxifylline; Vertebrata; Mammalia; Lung function; Animal; Respiratory distress; Xanthine derivatives; Lesion; Neutrophil; Dog
• ISSN: 0012-3692; 1931-3543
• DOI: 10.1378/chest.119.6.1893

We hypothesized that pentoxifylline, administered after phorbol myristate acetate (PMA), would diminish the severity of lung injury. Animal research laboratory. Comparative study. Mongrel dogs (n = 33). 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. 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. 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.