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Interleukin-2 induces early multisystem organ edema mediated by neutrophils
R Welbourn1, G Goldman, L Kobzik
1Department of Surgery, Harvard Medical School, Boston, Massachusetts.
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 10(6)U 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 (x10(3)/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 less than 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 less than 0.05). There was increased lung permeability demonstrated by bronchoalveolar lavage fluid protein concentration of 1970 +/- 210 micrograms/mL relative to control 460 +/- 90 micrograms/mL (p less than 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 less than 0.05) and increased plasma TxB2 levels to 1290 +/- 245 pg/mL relative to control 481 +/- 93 pg/mL (p less than 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 less than 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 +/- 220 micrograms/mL (p less than 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 less than 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.
Insights
Interleukin-2 (IL-2) infusion causes rapid lung and heart edema in rats by activating neutrophils (PMN). Depleting PMNs prevents this edema, indicating their central role in IL-2-induced fluid accumulation.
Area of Science:
- Immunology
- Pulmonary Medicine
- Pathophysiology
Background:
- Interleukin-2 (IL-2) is known to activate neutrophils (PMN), leading to thromboxane (Tx)B2 release and potential edema.
- The precise role of PMN in mediating IL-2-induced edema requires further investigation.
Purpose of the Study:
- To determine the role of neutrophils (PMN) in mediating pulmonary edema induced by Interleukin-2 (IL-2).
Main Methods:
- Anesthetized rats received intravenous infusions of recombinant human IL-2 or a vehicle control.
- Edema was assessed by lung wet to dry weight ratio and bronchoalveolar lavage fluid protein concentration.
- Neutrophil depletion was achieved using anti-rat neutrophil antiserum prior to IL-2 infusion.
Main Results:
- IL-2 infusion caused significant leukopenia, PMN sequestration in the lungs, and increased plasma TxB2 levels.
- Edema was observed in the lungs, heart, liver, and kidneys of IL-2-treated rats, with increased lung permeability.
- Pretreatment with neutrophil antiserum prevented lung and heart edema, reduced lung lavage protein, and inhibited TxB2 level increases.
Conclusions:
- Activated neutrophils (PMN) are the primary mediators of rapid lung and heart edema induced by Interleukin-2 (IL-2) infusion in rats.
- The study highlights the critical role of PMN activation and sequestration in IL-2-induced organ edema.