The rapid induction by interleukin-2 of pulmonary microvascular permeability.
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 10(5) 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 less than 0.05), and on Day 5, to 29 mmHg (p less than 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 less than 0.05) on Day 5. Lung lymph flow (QL) rose from 2.4 to 6.8 ml/30 minutes (p less than 0.05) on Day 1, and from 4.7 to 10.2 ml/30 minutes (p less than 0.05) on Day 5, whereas the lymph/plasma protein ratio increased on Day 1 from 0.69 to 0.83 (p less than 0.05) and from 0.63 to 0.71 (p less than 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 less than 0.05) and in lung lymph from 222 to 772 pg/ml (p less than 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 less than 0.05) during the 5 days of infusion. Systemic blood pressure did not change. Temperature rose from 39.1 to 41.2 C (p less than 0.05), and shaking chills were common. There was a progressive fall in leukocyte count, from 8.4 to 3.2 X 10(3)/mm3 (p less than 0.05) by Day 5, reflecting a 77% fall in lymphocytes. Lung lymph lymphocyte counts rose, and lymphocyte clearance increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
J M
JM
Klausner
N
N
Morel
I S
IS
Paterson
L
L
Kobzik
C R
CR
Valeri
T J
TJ
Eberlein
D
D
Shepro
H B
HB
Hechtman
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005402:Fistula / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D007376:Interleukin-2 / Q000493:pharmacokinetics*; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000098:blood supply*; D008196:Lymph / Q000187:drug effects*; D008197:Lymph Node Excision; D008214:Lymphocytes; D011506:Proteins / Q000032:analysis; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012131:Respiratory Insufficiency / Q000503:physiopathology*; D012756:Sheep; D013929:Thromboxane B2 / Q000032:analysis; D013997:Time Factors
D007376:Interleukin-2; D011506:Proteins; D011994:Recombinant Proteins; D013929:Thromboxane B2