Chronic interleukin-2 treatment in awake sheep causes minimal or no injury to the lung microvascular barrier

• Published in: Journal of applied physiology (1985) 1996-10, Vol.81 (4), p.1730-1738
• Main Authors: Jerome, E. Heidi, Enzan, Keiji, Douguet, Dominique, Lei, Dachuan, Jesmok, Gary, Johnson, Carol W, Neuburger, Maritza, Staub, Norman C
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Proteins - metabolism; Blood Volume - drug effects; Blood Volume - physiology; Blood-Air Barrier - drug effects; Extravascular Lung Water - drug effects; Hemodynamics - drug effects; Interleukin-2 - toxicity; Iodine Radioisotopes; Leukocyte Count - drug effects; Lung - pathology; Lymphatic System - drug effects; Medical sciences; Pneumology; Pulmonary Circulation - drug effects; Pulmonary Edema - chemically induced; Pulmonary Edema - pathology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Recombinant Proteins - pharmacology; Sheep
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/jappl.1996.81.4.1730

E. Heidi Jerome, Keiji Enzan, Dominique Douguet, Dachuan Lei, Gary Jesmok, Carol W. Johnson, Maritza Neuburger, and Norman C. Staub Departments of Anesthesia, Medicine, Physiology, and Cardiovascular Research Institute, University of California, San Francisco, California 94143-0542; and Cetus Corporation, Emeryville, California 94608 Received 23 May 1994; accepted in final form 21 May 1996. Jerome, E. Heidi, Keiji Enzan, Dominique Douguet, Dachuan Lei, Gary Jesmok, Carol W. Johnson, Maritza Neuburger, and Norman C. Staub. Chronic interleukin-2 treatment in awake sheep causes minimal or no injury to the lung microvascular barrier. J. Appl. Physiol. 81(4): 1730-1738, 1996. 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 cmH 2 O pre-IL-2, increased to 32 ± 4 cmH 2 O on the fourth day of IL-2, and returned to 29 ± 5 cmH 2 O 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 an 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. pulmonary edema; pulmonary circulation; lung injury 0161-7567/96