Interleukin-2 Induces Early Multisystem Organ Edema Mediated by Neutrophils

Abstract

Interleukin-2 (IL-2), an agent known to activate neutrophils (PMN) with thromboxane (Tx)B₂ release, produces pulmonary edema within 6 hours of intravenous infusion. This study tests the role of PMN in mediating the edema. Anesthetized rats received 10⁶U recombinant human IL-2 (n = 15) or vehicle (n = 14) as a constant intravenous infusion during a period of 1 hour. At this time there was leukopenia 3.63 ± 0.43 (x10³/mm³) relative to vehicle-infused control rats 6.12 ± 0.86 and a decline in PMN, 2.19 ± 0.14 relative to control value of 3.33 ± 0.05 (both p ≤ 0.05). After 6 hours edema, as measured by increase in the wet to dry weight (W/d) ratio, was present in the lungs (4.93 ± 0.20 relative to control 4.06 ± 0.10), heart (4.09 ± 0.11 versus 3.76 ± 0.08), liver (3.50 ± 0.10 versus 3.18 ± 0.10), and kidney (4.25 ± 0.07 versus 4.00 ± 0.07) (all p ≤ 0.05). There was increased lung permeability demonstrated by bronchoalveolarlavage fluid protein concentration of 1970 ± 210 Mg/mL relative to control 460 ± 90 μg/mL (p ≤ 0.05). Interleukin-2 resulted in lung 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 plasma TxB₂ levels to 1290 ± 245 pg/mL relative to control 481 ± 93 pg/mL (p ≤ 0.05). Pretreatment of other rats (n = 8) with selective anti-rat neutrophil antiserum 18 hours before the experiment led to a peripheral PMN count 10% of baseline and prevented edema in the lungs (W/d ratio 4.20 ± 0.16) and heart (3.67 ± 0.07) (both p ≤ 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 ± 220 ftg/mL (p ≤ 0.05). The protection afforded by leukopenia was associated with lack of PMN sequestration and prevention of the increase in plasma Tx levels (484 ± 120 pg/mL, p ≤ 0.05). These data indicate that the rapid induction of lung and heart edema with a 1-hour infusion of IL-2 in the rat is mediated, in large part, by activated PMNs.