Liposome-induced pulmonary hypertension:: properties and mechanism of a complement-mediated pseudoallergic reaction
Liposome-induced pulmonary hypertension:: properties and mechanism of a complement-mediated pseudoallergic reaction
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DOI：
10.1152/ajpheart.2000.279.3.h1319
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发表时间：
2000-09-01
影响因子：
4.8
通讯作者：
Alving, CR
中科院分区：
文献类型：
--
作者：
Szebeni, J;Baranyi, L;Alving, CR
静脉注射脂质体可引起猪的显著肺动脉高压，这是一种血管收缩反应，为某些脂质体药物引起的人类心肺窘迫提供了敏感模型。该反应最近被证明是“补体激活相关的假变态反应”的表现（CARPA; Szebeni J，丰塔纳JL，Wassef NM，Mongan PD，莫尔斯DS，Dobbins DE，斯塔尔GL，Bunger R和Alving CR. Circulation 99：2302-2309，1999）。在本研究中，我们证明了脂质体的组成、大小和给药方法对肺血管活性有显著影响，其在瞬时致死（推注5 mg脂质后）至不可检测（尽管输注了2,000倍的高剂量）之间变化。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vs.缓慢输注。用人C3 a、C5 a和异种反应性免疫球蛋白再现大多层脂质体的血管活性，并且其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 mm的单层单分散脂质体无显著血管活性。这些数据表明，脂质体诱导的猪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，它可以通过适当的剪裁囊泡的结构和给药方法来预防。
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, Bunger 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 mm 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.