Szebeni János, Baranyi Lajos, Sávay Sándor, Bodó Michael, Milosevits János, Alving Carl R, Bünger Rolf
Division of Retrovirology, Department of Vaccine Production and Delivery, United States Military Human Immunodeficiency Virus Research Program, 1600 E. Gude Dr., Rockville, Maryland 20850, USA.
Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1050-8. doi: 10.1152/ajpheart.00622.2005. Epub 2005 Oct 7.
Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A1 receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A(2) blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A1 receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A1-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.
心脏过敏反应是对过敏原和药物的急性超敏反应的一种严重的、危及生命的表现形式。早期研究强调了局部应用C5a在该过程中的放大作用；然而，血液中系统性补体（C）激活及C5a释放的作用迄今尚未得到探索。在本研究中，我们使用猪脂质体诱导的心肺窘迫模型来：1）表征和量化外周C激活相关的心脏功能障碍；2）探索C5a在心脏异常中的作用以及可溶性C1型受体（sCR1）和抗C5a抗体（GS1）阻断C的治疗潜力；3）阐明腺苷和腺苷受体在矛盾性心动过缓中的作用，矛盾性心动过缓是该模型中观察到的症状之一。给猪静脉注射不同的脂质体[阿霉素脂质体和多层囊泡（MLV）]、酵母聚糖、重组人（rhu）C5a和腺苷，并通过任意评分[心脏异常评分（CAS）]对随后的血流动力学和心脏变化（低血压、心动过速或心动过缓、心律失常、ST-T改变、心室颤动和心脏停搏）进行量化。CAS与脂质体在体外产生C5a之间存在显著相关性，并且酵母聚糖、rhuC5a、腺苷和选择性腺苷A1受体激动剂环戊基腺苷部分或完全重现了脂质体诱导的心脏异常。使用C非激活剂脂质体或用sCR1或GS1对猪进行预处理可减轻这些异常。选择性A1阻断剂环戊基黄嘌呤抑制心动过缓而不影响低血压，而A2阻断剂4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚（ZM-24135）则没有这种作用。这些数据表明：1）系统性C激活可能是心脏过敏反应的基础；2）C5a在该反应中起因果作用；3）通过A1受体的腺苷作用可能解释矛盾性心动过缓；4）抑制C5a的形成或作用或A1受体功能可能减轻脂质体药物和其他激活C的静脉内药物的急性心脏毒性。
