Lung vascular effects of phorbol myristate acetate in awake sheep

Abstract

Phorbol myristate acetate [an ester derivative of croton oil] (PMA) activates granulocytes in vitro, stimulating oxidative metabolism, aggregation and specific degranulation. To determine the effects of in vivo granulocyte stimulation on the pulmonary circulation, we infused PMA (5 .mu.g/kg) as an i.v. bolus into 6 awake sheep surgically prepared for chronic hemodynamic measurements and lung lymph collection. PMA caused leukocyte counts to decrease from 5250 .+-. 363 (SE) to 2450 .+-. 224 cell/mm3. Platelet counts did not change. After PMA, all sheep developed respiratory distress which lasted several h. Mean pulmonary arterial pressure rose from 14 .+-. 1 (SE) to an initial peak of 51 .+-. 3 cmH2O within several min, and remained elevated for 4 h before returning to near base line (18 .+-. 2); arterial PO2 [partial pressure O2] (PaO2) fell from a base line of 90 .+-. 2 (SE) to 59 .+-. 6 Torr at 15 min. Lung lymph flow increased from 2.4 .+-. 0.5 (SE) to peak at 8.2 .+-. 1.1 ml/15 min within the first 30-45 min after PMA and then slowly decreased to levels twice base line at 6 h after PMA. Lymph-to-plasma protein concentration ratio fell initially after PMA, then returned to base line levels after 3 h. The high flow of protein-rich lymph 3-5 h after PMA suggests an increase in pulmonary vascular permeability. Lung lymph thromboxane B2 (TXB2) and 6-keto-prostaglandin F1.alpha. concentrations rose dramatically within 1 h after PMA, and pulmonary arterial pressure correlated closely with lymph TXB2 concentrations at 1 h. In 1 anesthetized sheep, lung granulocyte counts increased 8-fold 1.5 h after PMA. PMA infusion in the awake sheep causes initial pulmonary hypertension and a later period of apparently increased pulmonary vascular permeability. The reaction is similar to that caused by Escherichia coli endotoxin infusion.