Klausner J M, Paterson I S, Morel N M, Goldman G, Gray A D, Valeri R, Eberlein T J, Shepro D, Hechtman H B
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Cancer Res. 1989 Jul 1;49(13):3542-9.
Interleukin (IL)-2 administration leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of thromboxane (Tx)A2 in IL-2 induced lung injury in sheep with chronic lung lymph fistulae. This preparation enables evaluation of permeability prior to the development of gross edema. IL-2, 10(5) units/kg (n = 6), or its excipient control (n = 5) was given as an i.v. bolus over 2 min. After 2 h of IL-2 administration, plasma TxB2 increased from 168 to 388 pg/ml (P less than 0.05) and lung lymph TxB2 from 235 to 694 pg/ml (P less than 0.05). Mean pulmonary artery pressure (MPAP) rose from 13 to 29 mm of Hg (P less than 0.05) at 30 min and remained elevated for 4 h while the pulmonary artery wedge pressure was unchanged at 4 mm of Hg. Arterial oxygen tension (PaO2) fell from 88 to 77 mm of Hg (P less than 0.05). Lung lymph flow (QL) rose from 2.2 to 3.8 ml/30 min (P less than 0.05) at 1 h and to 6.4 ml/30 min at 3 h. This rise coincided with an increase in the lymph/plasma (L/P) protein ratio from 0.67 to 0.77 (P less than 0.05). In contrast, the non-IL-2-infused sheep (n = 3) recruitment of the lung vasculature by left atrial balloon inflation led to a rise in QL from 2.4 to 8.2 ml/30 min, whereas the L/P ratio declined from 0.62 to 0.25, suggesting that the protein-rich lymph flow after IL-2 administration reflected increased microvascular permeability. In further proof of an increase in permeability, IL-2 administration into sheep (n = 2) with an inflated left atrial balloon led, after a pressure-independent L/P protein ratio had been achieved, to an increase in L/P protein ratio and decrease in protein reflection coefficient. At 2 h after IL-2, the blood leukocyte count fell from 8156 to 4375/mm3 (P less than 0.05) primarily due to a 73% drop in lymphocytes. The platelet count declined from 292 to 184 x 10(3)/mm3 (P less than 0.05). Body temperature rose from 38.9-40.3 degrees C (P less than 0.05), and shaking chills were common. Pretreatment with the Tx synthetase inhibitor OKY 046 (n = 7) lowered baseline plasma and lymph TxB2 levels to 22 and 52 pg/ml (P less than 0.05) and prevented the IL-2-induced increase in plasma and lung lymph TxB2 (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
由于血管通透性增加，给予白细胞介素（IL）-2会导致呼吸功能障碍。本研究探讨了血栓素（Tx）A2在慢性肺淋巴瘘绵羊中IL-2诱导的肺损伤中的作用。这种制备方法能够在出现明显水肿之前评估通透性。以静脉推注方式在2分钟内给予IL-2，剂量为10(5)单位/千克（n = 6），或其赋形剂对照（n = 5）。给予IL-2 2小时后，血浆TxB2从168 pg/ml升至388 pg/ml（P < 0.05），肺淋巴TxB2从235 pg/ml升至694 pg/ml（P < 0.05）。平均肺动脉压（MPAP）在30分钟时从13 mmHg升至29 mmHg（P < 0.05），并在4小时内持续升高，而肺动脉楔压在4 mmHg保持不变。动脉血氧张力（PaO2）从88 mmHg降至77 mmHg（P < 0.05）。肺淋巴流量（QL）在1小时时从2.2 ml/30分钟升至3.8 ml/30分钟（P < 0.05），在3小时时升至6.4 ml/30分钟。这种升高与淋巴/血浆（L/P）蛋白比值从0.67升至0.77（P < 0.05）同时出现。相比之下，未输注IL-2的绵羊（n = 3）通过左心房球囊充气使肺血管床扩张，导致QL从2.4 ml/30分钟升至8.2 ml/30分钟，而L/P比值从0.62降至0.25，这表明给予IL-2后富含蛋白质的淋巴流量反映了微血管通透性增加。为进一步证明通透性增加，在左心房球囊充气的绵羊（n = 2）中给予IL-2，在达到压力无关的L/P蛋白比值后，导致L/P蛋白比值增加且蛋白反射系数降低。给予IL-2 2小时后，血液白细胞计数从8156/mm3降至4375/mm3（P < 0.05），主要是由于淋巴细胞减少73%。血小板计数从292×10(3)/mm3降至184×10(3)/mm3（P < 0.05）。体温从38.9℃升至40.3℃（P < 0.05），寒战常见。用Tx合成酶抑制剂OKY 046预处理（n = 7）可将基线血浆和淋巴TxB2水平降至22 pg/ml和52 pg/ml（P < 0.05），并防止IL-2诱导的血浆和肺淋巴TxB2增加（P < 0.05）。（摘要截断于400字）
