Phorbol myristate acetate lung injury and airway responsiveness to aerosol histamine in awake sheep

Abstract

To test the hypothesis that phorbol myristate acetate (PMA), a potent granulocyte activator, would increase airway responsiveness to aerosol histamine, we quantitated airway responsiveness to aerosol histamine in nine awake sheep before and 4 1 2 hours after intravenous PMA, 5 μg/kg. A dose-response curve to aerosol histamine was constructed by administering histamine aerosols of 0.1, 0.3, 1.0, 3.0, 10.0, and 30.0 mg/ml sequentially until dynamic lung compliance (C dyn) decreased to ⩽65% baseline. The dose of histamine that caused a reduction of C dyn to 65% of baseline (ED 65C dyn) was determined by linear interpolation. We then administered PMA, defined a new baseline C dyn 4 1 2 hours later, and administered aerosol histamine as before. Control experiments were performed on another day in eight of the nine sheep by administering aerosol histamine 4 1 2 hours apart without infusing PMA. Histamine responsiveness did not change significantly during 4 1 2 hours in the control experiments. Control (preaerosol histamine) C dyn decreased from 0.090 ± 0.010 L/cm H 2O before PMA to 0.048 ± 0.004 L/cm H 2 4 1 2 hours after PMA. The mean pre-PMA ED 65 C dyn for the nine sheep was 3.80 ± 0.87 mg/ml, and the mean post-PMA ED 65C dyn was 2.13 ± 0.98 mglml ( p < 0.05). When individual doseresponse curves are examined, the small statistical increase in aerosol histamine responsiveness does not appear important, especially when the increase is compared to the changes previously reported after endotoxemia in unanesthetized sheep.