Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2

Immunotherapy with the lymphokine interleukin-2 (IL-2), with or without lymphokine activated killer (LAK) cells, offers a new approach to the treatment of solid tumors. Unfortunately, most patients receiving IL-2 and LAK cells develop a "third space syndrome" from a presumed generalized increase of vascular permeability. We have investigated the role of IL-2 on lung fluid balance, by measuring changes in lung water and albumin intake. Rats were injected with IL-2 500,000 U i.p. three times a day for 1 to 4 days. At the completion of the injections, lungs were isolated and perfused, and total lung water (TLW) and 125I-albumin uptake were measured. After 1 day of injections, TLW increased from 4.90 +/- 0.14 to 5.57 +/- 0.34 ml/g dry lung and albumin uptake nearly doubled from 0.47 +/- 0.08 to 0.91 +/- 0.28 cm3/s/g dry lung X 10(-3). Longer injection periods increased both TLW and albumin uptake further. After 2 days, TLW and albumin uptake were also significantly increased by 160,000 U i.p. three times a day, but not by 40,000 or 10,000 U. To eliminate possible contributions to increased permeability by (a) LAK cells generated in vivo, or (b) circulating leukocytes, we isolated lungs from normal rats and perfused them for 5 min with a cell-free perfusate containing IL-2 (2, 10, or 5 X 10(-3) U/ml) excipient or 0.9% NaCl placebo. TLW was similar in all groups, but albumin uptake was significantly increased by 10,000 and 50,000 U/ml (0.94 +/- 0.15 and 0.82 +/- 0.16 cm3/s/g dry lung X 10(-3), respectively), but not by 2,000 U/ml. We conclude that lung microvascular albumin permeability is increased following administration of IL-2 in vivo and in vitro. We suggest that LAK cells are not required for the initiation of increased permeability and that IL-2 may have some direct effect on the pulmonary microvasculature.