Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: A model for pseudoallergic cardiopulmonary reactions to liposomes: Role of complement and inhibition by soluble CR1 and anti-C5a antibody

Janos Szebeni, John L. Fontana, Nabila M. Wassef, Paul D. Mongan, David S. Morse, David E. Dobbins, Gregory L. Stahl, Rolf Bünger, Carl R. Alving

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Abstract

Background - 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. Methods and Results - 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. Conclusions - 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).

Original languageEnglish
Pages (from-to)2302-2309
Number of pages8
JournalCirculation
Volume99
Issue number17
DOIs
Publication statusPublished - May 4 1999

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Keywords

  • Blood cells
  • Hemodynamics
  • Hypertension, pulmonary
  • Immune system
  • Thromboxane

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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