Szebeni J, Fontana J L, Wassef N M, Mongan P D, Morse D S, Dobbins D E, Stahl G L, Bünger R, Alving C R
Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC, USA.
Circulation. 1999 May 4;99(17):2302-9. doi: 10.1161/01.cir.99.17.2302.
Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified.
Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (P<0.01) alterations included 79+/-9% (mean+/-SEM) rise in pulmonary arterial pressure, 30+/-7% decline in cardiac output, 11+/-2% increase in heart rate, 236+/-54% increase in pulmonary vascular resistance, 71+/-27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B2. These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose-dependent (ED50=4. 5+/-1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B2 and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes.
The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation-related pseudoallergy" (CARPA).
静脉注射某些脂质体药物可引发即刻超敏反应，包括心肺窘迫症状。心血管变化的潜在机制尚未阐明。
对18头麻醉猪静脉注射5毫克大单层脂质体推注剂量，记录随后的血流动力学、血液学和实验室变化。显著（P<0.01）变化包括肺动脉压升高79±9%（平均值±标准误）、心输出量下降30±7%、心率增加11±2%、肺血管阻力增加236±54%、全身血管阻力增加71±27%，血浆血栓素B2增加高达100倍。这些变化在注射后1至5分钟达到峰值，在10至20分钟内消退，呈脂质剂量依赖性（半数有效剂量=4.5±1.4毫克），并且在7小时内可在同一动物身上多次定量重复出现。脂质体诱导的肺动脉压升高与血浆血栓素B2升高在数量和时间上密切相关，并被抗C5a单克隆抗体（GS1）、sCR1或吲哚美辛抑制。脂质体通过经典途径激活在猪血清中产生C5a，并结合IgG和IgM天然抗体。含酵母聚糖和血红蛋白的脂质体以及空脂质体引起的肺部变化基本相同。
微量静脉注射脂质体在猪身上产生的强烈、无快速耐受性、高度可重复、补体介导的肺动脉高压效应代表了循环生理学中一种独特的、未被探索的现象。该模型为检测和研究脂质体药物及许多其他药品因“补体激活相关假过敏”（CARPA）导致的心肺副作用提供了高度敏感的方法。
