Involvement of thromboxane and neutrophils in multiple-system organ edema with interleukin-2.
Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.
Welbourn
R
R
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Goldman
G
G
Kobzik
L
L
Valeri
C R
CR
Shepro
D
D
Hechtman
H B
HB
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000473:pathology; D004487:Edema / Q000503:physiopathology*; D006331:Heart Diseases / Q000503:physiopathology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D007674:Kidney Diseases / Q000503:physiopathology; D008107:Liver Diseases / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D011654:Pulmonary Edema / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000097:blood
D007376:Interleukin-2; D011994:Recombinant Proteins; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha