Szebeni J, Baranyi L, Savay S, Bodo M, Morse D S, Basta M, Stahl G L, Bünger R, Alving C R
Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, District of Columbia 20307, USA.
Am J Physiol Heart Circ Physiol. 2000 Sep;279(3):H1319-28. doi: 10.1152/ajpheart.2000.279.3.H1319.
Intravenous injection of liposomes can cause significant pulmonary hypertension in pigs, a vasoconstrictive response that provides a sensitive model for the cardiopulmonary distress in humans caused by some liposomal drugs. The reaction was recently shown to be a manifestation of "complement activation-related pseudoallergy" (CARPA; Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bünger R, and Alving CR. Circulation 99: 2302-2309, 1999). In the present study we demonstrate that the composition, size, and administration method of liposomes have significant influence on pulmonary vasoactivity, which varied between instantaneously lethal (following bolus injection of 5 mg lipid) to nondetectable (despite infusion of a 2,000-fold higher dose). Experimental conditions augmenting the pulmonary hypertensive response included the presence of dimyristoyl phosphatidylglycerol, 71 mol% cholesterol, distearoyl phosphatidylcholine, and hemoglobin in liposomes, increased vesicle size and polydispersity, and bolus injection vs. slow infusion. The vasoactivity of large multilamellar liposomes was reproduced with human C3a, C5a, and xenoreactive immunoglobulins, and it correlated with the complement activating and natural antibody binding potential of vesicles. Unilamellar, monodisperse liposomes with 0.19 +/- 0.10 microm mean diameter had no significant vasoactivity. These data indicate that liposome-induced pulmonary hypertension in pigs is multifactorial, it is due to natural antibody-triggered classic pathway complement activation and it can be prevented by appropriate tailoring of the structure and administration method of vesicles.
静脉注射脂质体可导致猪出现显著的肺动脉高压，这种血管收缩反应为某些脂质体药物引起的人类心肺窘迫提供了一个敏感模型。最近的研究表明，这种反应是“补体激活相关假过敏”（CARPA；Szebeni J、Fontana JL、Wassef NM、Mongan PD、Morse DS、Dobbins DE、Stahl GL、Bünger R和Alving CR。《循环》99: 2302 - 2309，1999）的一种表现。在本研究中，我们证明脂质体的组成、大小和给药方式对肺血管活性有显著影响，其变化范围从即刻致死（推注5 mg脂质后）到无法检测到（尽管输注剂量高出2000倍）。增强肺动脉高压反应的实验条件包括脂质体中存在二肉豆蔻酰磷脂酰甘油、71 mol%胆固醇、二硬脂酰磷脂酰胆碱和血红蛋白，囊泡大小和多分散性增加，以及推注与缓慢输注。大的多层脂质体的血管活性可由人C3a、C5a和异种反应性免疫球蛋白重现，并且它与囊泡的补体激活和天然抗体结合潜力相关。平均直径为0.19 +/- 0.10微米的单层、单分散脂质体没有显著的血管活性。这些数据表明，猪中脂质体诱导的肺动脉高压是多因素的，它是由于天然抗体触发的经典途径补体激活，并且可以通过适当调整囊泡的结构和给药方式来预防。
