Submitted on June 10, 2005
Accepted on September 27, 2005
Complement A ctivation-Related Cardiac Anaphylaxis in Pigs: Role of C5a Anaphylatoxin and Adenosine in Liposome-Induced Abnormalities in ECG and Heart Function
Janos Szebeni1*, Lajos Baranyi2, Sandor Savay2, Michael Bodo3, Janos Milosevits4, Carl R Alving1, and Rolf Bunger5
1 Department of Vaccine Production and Delivery, Walter Reed Army Institute of Research, US Military HIV Research Program, Rockville, MD, USA
2 Vaccine and Immunology Research Institute, Washington, DC, USA
3 Department of Resuscitation Medicine, Walter Reed Army Institute of Research, Washington, DC, USA
4 Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC, USA
5 Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: jszebeni{at}hivresearch.org, jszebeni@aol.com.
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 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 i.v. with different liposomes (Doxil, MLV), zymosan, rhuC5a 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 A1 agonist cyclopentyl-adenosine. The use of C non-activator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, while the A2 blocker ZM24135 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.
