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, 10⁵ U (n = 7), 10⁶ 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 10⁵ U IL-2 and in the lung, heart, liver and kidney with 10⁶ U IL-2, relative to values with vehicle-infused controls (all p < 0.05). With a 1-hour infusion of 10⁶ 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 < 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 ± 7 PMN/10 high-power fields (HPF) relative to 23 ± 2 PMN/10 HPF in controls (p < 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 ± 210 μg/mL relative to 460 μg/mL in controls (p < 0.05). When 10⁶ 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.