Chronic interleukin-2 treatment in awake sheep causes minimal or no injury to the lung microvascular barrier.
Interleukin-2 (IL-2) is reputed to cause a "vascular leak syndrome." We studied pulmonary hemodynamics and lymph dynamics in six sheep treated for 7 days with IL-2 (1.8 million IU/kg twice daily or 1.8 million IU/kg each day as a continuous infusion). Lung lymph flow increased from 4.8 +/- 2 ml/15 min pre-IL-2 to 14.4 +/- 6.8 ml/15 min on the seventh day of IL-2. The lymph-to-plasma protein concentration ratio was unchanged (0.70 +/- 0.06 vs. 0.63 +/- 0.13). The plasma-to-lymph equilibration half-time of radiolabeled albumin was 2.0 +/- 0.6 h pre-IL-2 and 1.0 +/- 0.7 h on day 7 of IL-2. Pulmonary arterial pressure was 24 +/- 7 cmH2O pre-IL-2, increased to 32 +/- 4 cmH2O on the fourth day of IL-2, and returned to 29 +/- 5 cmH2O on the seventh day of IL-2. Extravascular lung water was normal (4.07 +/- 0.25 g/g dry lung). To clearly determine whether the increase in lung lymph flow was due to hemodynamic changes or to increased leakiness of the microvascular barrier, we volume loaded six sheep with lactated Ringer solution before and after 3 days of IL-2 treatment (1.8 million IU/kg twice daily). Lung lymph flows increased fivefold during 4 h of crystalloid infusion compared with baseline and were higher after 3 days of IL-2. However, lymph-to-plasma protein concentration ratios decreased to the same low levels pre-and post IL-2 (0.39 +/- 0.06 vs. 0.41 +/- 0.10), indicating and intact microvascular barrier. Extravascular lung water was elevated (5.56 +/- 0.39 g/g dry lung) but was not different from lung water in three volume-loaded control sheep (4.87 +/- 0.53 g/G dry lung). We conclude that IL-2 causes minimal or no injury to the pulmonary microvascular barrier and that volume expansion during IL-2 treatment can cause hydrostatic pulmonary edema.
Department of Anesthesia, University of California, San Francisco 94143-0542, USA.
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EH
Jerome
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Enzan
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Douguet
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Lei
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Jesmok
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CW
Johnson
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Neuburger
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NC
Staub
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001810:Blood Volume / Q000187:drug effects / Q000502:physiology; D015824:Blood-Air Barrier / Q000187:drug effects*; D015633:Extravascular Lung Water / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007376:Interleukin-2 / Q000633:toxicity*; D007457:Iodine Radioisotopes; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000473:pathology; D008208:Lymphatic System / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D012756:Sheep
D001798:Blood Proteins; D007376:Interleukin-2; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins