Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy.

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

doi:10.3390/molecules24183283

László Dézsi, Péter Hamar + Show 7 more

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https://doi.org/10.3390/molecules24183283

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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.

Highlights

One of the promising new directions in pharmacotherapy is the use of nanoparticulate vehicles for controlled, targeted drug delivery [1,2]
Complement Activation by the Different Reaction Inducers. Both zymosan and cobra venom factor (CVF) caused massive C activation in rat blood, the extent and kinetics of changes were different for the two activators (Figure 1A)
AmBisome, at a high dose, caused significant C activation (Figure 1B), while unexpectedly, the AmBisome-equivalent drug-free liposome AmBisombo and polyethylene glycol (PEG)-2000-chol liposomes did not, even at high concentrations (Figure 1C). This suggests that amphotericin B had a key role in engendering AmBisome liposomes with C activator capability, at least in rat blood in vivo, and that PEG-2000-chol, which was found to be a strong C activator in human serum [18], is not displaying this activity in rats in vivo

Summary

Introduction

One of the promising new directions in pharmacotherapy is the use of nanoparticulate vehicles for controlled, targeted drug delivery [1,2]. Recent studies in pigs [8] and mice [9] raised the possibility of C-independent mechanisms as well, referred to as C-independent pseudoallergy (CIPA) At this time, we cannot exclude the possibility that the apparent absence of C activation in these cases was due to assay failure, such as low sensitivity and/or improper test and/or incorrect sampling times, and, C activation was present, just not detected. We cannot exclude the possibility that the apparent absence of C activation in these cases was due to assay failure, such as low sensitivity and/or improper test and/or incorrect sampling times, and, C activation was present, just not detected An example for the latter possibility was seen in the case of polystyrene nanoparticle-induced

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