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Open AccessArticle

The Involvement of the RhoA/ROCK Signaling Pathway in Hypersensitivity Reactions Induced by Paclitaxel Injection

Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(20), 4988; https://doi.org/10.3390/ijms20204988
Received: 13 September 2019 / Revised: 29 September 2019 / Accepted: 30 September 2019 / Published: 9 October 2019
(This article belongs to the Section Molecular Toxicology)
A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects. View Full-Text
Keywords: paclitaxel injection; hypersensitivity reactions; vascular permeability; histamine release; complement activation; RhoA/ROCK signaling pathway paclitaxel injection; hypersensitivity reactions; vascular permeability; histamine release; complement activation; RhoA/ROCK signaling pathway
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Pan, C.; Zhang, Y.-S.; Han, J.-Y.; Li, C.-Y.; Yi, Y.; Zhao, Y.; Wang, L.-M.; Tian, J.-Z.; Liu, S.-Y.; Li, G.-Q.; Li, X.-L.; Xian, Z.; Liang, A.-H. The Involvement of the RhoA/ROCK Signaling Pathway in Hypersensitivity Reactions Induced by Paclitaxel Injection. Int. J. Mol. Sci. 2019, 20, 4988.

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