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ID 115154
Title Alternative
Contribution of CARPA to polystyrene NP effects in pigs
Author
Mészáros, Tamás Semmelweis University|SeroScience
Kozma, Gergely Tibor SeroScience
Miyahara, Koga Tokushima University
Turjeman, Keren The Hebrew University-Hadassah Medical School
Barenholz, Yechezkel The Hebrew University-Hadassah Medical School
Urbanics, Rudolf Semmelweis University|SeroScience
Szebeni, János Semmelweis University|SeroScience|Miskolc University
Keywords
adverse drug reactions
immunotoxicity
nanoparticles
pseudoallergy
anaphylatoxins
PIM cells
phagocytosis
Content Type
Journal Article
Description
Background: It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions.
Goals: To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs.
Study design: C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo.
Methods: Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model.
Results: PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs.
Conclusion: PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the “double-hit” concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy.
Journal Title
International Journal of Nanomedicine
ISSN
11782013
NCID
AA1215861X
Publisher
Dove Medical Press
Volume
13
Start Page
6345
End Page
6357
Published Date
2018-10-11
Rights
© 2018 Mészáros et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
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language
eng
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departments
Pharmaceutical Sciences