Complement activation-related pathophysiological changes in anesthetized rats: Activator-dependent variations of symptoms and mediators of pseudoallergy

László Dézsi, Tamás Mészáros, Erik Orfi, Tamás G. Fülöp, Mark Hennies, László Rosivall, Péter Hamar, János Szebeni, Gábor Szénási

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.

Original languageEnglish
Article number3283
JournalMolecules
Volume24
Issue number18
DOIs
Publication statusPublished - Sep 9 2019

Keywords

  • Amphotericin B
  • Blood cell count
  • Blood pressure
  • Cobra venom factor
  • Complement activation
  • Infusion reactions
  • Thromboxane
  • Zymosan

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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