Klausner J M, Paterson I S, Goldman G, Kobzik L, Lelcuk S, Skornick Y, Eberlein T, Valeri C R, Shepro D, Hechtman H B
Department of Surgery, Brigham & Women's Hospital, Boston, Mass.
Surgery. 1991 Feb;109(2):169-75.
Interleukin-2 therapy leads to respiratory dysfunction caused by increased vascular permeability. This study examines the role of oxygen-derived free radicals (OFR). Sheep (n = 6) with chronic lung lymph fistulae were given interleukin-2, 10(5) units/kg, as an intravenous bolus. The mean pulmonary artery pressure rose from 13 to 23 mm Hg (p less than 0.05) at 1 hour and remained elevated for 4 hours, although the pulmonary artery wedge pressure was unchanged at 4 mm Hg. Arterial oxygen tension fell from 88 to 77 mm Hg (p less than 0.05). Lung lymph flow rose from 2.2 to 6.4 ml/30 min (p less than 0.05) at 3 hours. This rise coincided with an increase in the lymph/plasma protein ratio from 0.67 to 0.77 (p less than 0.05) and lymph protein clearance from 1.5 to 4.4 ml/30 min (p less than 0.05), indicating increased lung microvascular permeability. Interleukin-2 led to transient increases in plasma thromboxane B2 from 168 to 388 pg/ml (p less than 0.05) and lung lymph thromboxane B2 from 235 to 694 pg/ml (p less than 0.05). The leukocyte count fell from 8156 to 4375/mm3 (p less than 0.05) primarily caused by a 78% drop in lymphocyte count. Platelet count declined from 292 to 184 X 10(3)/mm3 (p less than 0.05). Pretreatment with the hydroxyl radical scavenger dimethylthiourea, 1 gm/kg, intravenously, (n = 6) prevented the interleukin-2-induced increase in mean pulmonary artery pressure, lung lymph flow, lymph/plasma protein ration, lymph protein clearance, and thromboxane B2 levels in plasma and lung lymph. The arterial oxygen tension decreased from 85 to 80 mm Hg (p less than 0.05). The leukocyte count declined from 7854 to 6229/mm3 (p less than 0.05), but this was not as low nor as prolonged as the interleukin-2 group. Further, the decrease in platelet count was prevented (p less than 0.05). Interleukin-2 incubated with sheep or human leukocytes led to a dose-dependent increase in intracellular hydrogen peroxide production by neutrophils as measured by flow cytometry of dichlorofluorescein oxidation. These data indicate that interleukin-2 stimulates OFR generation and that OFR moderate the interleukin-2-induced increased lung permeability.
白细胞介素 -2 治疗会导致因血管通透性增加而引起的呼吸功能障碍。本研究探讨氧衍生自由基（OFR）的作用。对患有慢性肺淋巴瘘的绵羊（n = 6）静脉推注 10⁵ 单位/千克的白细胞介素 -2。平均肺动脉压在 1 小时时从 13 毫米汞柱升至 23 毫米汞柱（p < 0.05），并在 4 小时内持续升高，尽管肺动脉楔压在 4 毫米汞柱时未发生变化。动脉血氧分压从 88 毫米汞柱降至 77 毫米汞柱（p < 0.05）。肺淋巴流量在 3 小时时从 2.2 毫升/30 分钟升至 6.4 毫升/30 分钟（p < 0.05）。这种升高与淋巴/血浆蛋白比值从 0.67 增至 0.77（p < 0.05）以及淋巴蛋白清除率从 1.5 毫升/30 分钟增至 4.4 毫升/30 分钟（p < 0.05）同时出现，表明肺微血管通透性增加。白细胞介素 -2 导致血浆血栓素 B₂ 从 168 皮克/毫升短暂升至 388 皮克/毫升（p < 0.05），肺淋巴血栓素 B₂ 从 235 皮克/毫升升至 694 皮克/毫升（p < 0.05）。白细胞计数从 8156/立方毫米降至 4375/立方毫米（p < 0.05），主要是由于淋巴细胞计数下降了 78%。血小板计数从 292×10³/立方毫米降至 184×10³/立方毫米（p < 0.05）。用羟基自由基清除剂二甲基硫脲 1 克/千克静脉预处理（n = 6）可防止白细胞介素 -2 诱导的平均肺动脉压、肺淋巴流量、淋巴/血浆蛋白比值、淋巴蛋白清除率以及血浆和肺淋巴中血栓素 B₂ 水平的升高。动脉血氧分压从 85 毫米汞柱降至 80 毫米汞柱（p < 0.05）。白细胞计数从 7854/立方毫米降至 6229/立方毫米（p < 0.05），但不如白细胞介素 -2 组那么低且持续时间也没有那么长。此外，血小板计数的下降得到了预防（p < 0.05）。通过二氯荧光素氧化的流式细胞术测量，白细胞介素 -2 与绵羊或人白细胞孵育会导致中性粒细胞内过氧化氢生成呈剂量依赖性增加。这些数据表明白细胞介素 -2 刺激 OFR 的产生，并且 OFR 调节白细胞介素 -2 诱导的肺通透性增加。
