The clinical use of interleukin-2 (IL-2) is limited by severe cardiopulmonary dysfunction. This study examines the mechanism of respiratory failure related to IL-2, using sheep with chronic lung lymph fistulae. Awake animals were infused with an intravenous (I.V.) bolus of IL-2 105 U/kg (n = 5) or its excipient (EXC) control (n = 3), every 8 hours for 4 to 5 days. Cardiopulmonary function was monitored daily for at least one 8-hour period. Within 2 hours after each IL-2 administration, mean pulmonary arterial pressure (MPAP) rose. On Day 1, the mean rise was from 13 to 26 mmHg (p < 0.05), and on Day 5, to 29 mmHg (p < 0.05). MPAP returned to baseline levels after 2-3 hours. Pulmonary arterial wedge pressure was unchanged from 4 mmHg. There were transient falls in arterial oxygen tension, from 88 to 77 mmHg on Day 1 and to 73 mmHg (p < 0.05) on Day 5. Lung lymph flow (Q̇L) rose from 2.4 to 6.8 ml/30 minutes (p < 0.05) on Day 1, and from 4.7 to 10.2 ml/30 minutes (p < 0.05) on Day 5, whereas the lymph/plasma protein ratio increased on Day 1 from 0.69 to 0.83 (p < 0.05) and from 0.63 to 0.71 (p < 0.05) on Day 5. This documents an increase in pulmonary microvascular permeability. Thromboxane (Tx)B2 levels increased transiently after each IL-2 injection in plasma from 195 to 340 pg/ml (p < 0.05) and in lung lymph from 222 to 772 pg/ml (p < 0.05) on Day 1, and to similar levels on Day 5. There was a progressive rise in cardiac output from 5.7 to 8.6 1/minute (p < 0.05) during the 5 days of infusion. Systemic blood pressure did not change. Temperature rose from 39.1 to 41.2 C (p < 0.05), and shaking chills were common. There was a progressive fall in leukocyte count, from 8.4 to 3.2 x 103/mm3 (p < 0.05) by Day 5, reflecting a 77% fall in lymphocytes. Lung lymph lymphocyte counts rose, and lymphocyte clearance increased. Lung histology revealed lymphocyte sequestration in capillary beds and peribronchial areas. EXC control infusions resulted in mild fever, increase in MPAP from 12 to 17 mmHg (p 0.05), and Q̇L from 2.6 to 5.1 ml/30 minutes, along with a fall in the L/P protein ratio from 0.77 to 0.71 (p < 0.05) - changes that did not indicate increased permeability and were noted only on Day 1. The effect of IL-2 on endothelial cell (EC) barrier function was studied directly using bovine aortic EC grown to confluence on microcarrier beads. The EC barrier to the passage of trypan blue conjugated to albumin from the cultured mediun into the microcarrier matrix was not altered by IL-2 (1-104 U/ml) or EXC. These data indicate that IL-2 leads to lung injury manifest by pulmonary hypertension and rapid increase in lung vascular permeability, effects likely mediated by lymphocytes and Tx. IL-2 alone has no direct effect on the vascular barrier.