Schremmer, C, Steinritz, D, Gudermann, T et al. (2 more authors) (2022) An ex vivo perfused ventilated murine lung model suggests lack of acute pulmonary toxicity of the potential novel anticancer agent (−)-englerin A. Archives of Toxicology, 96 (4). pp. 1055-1063. ISSN 0340-5761
Abstract
(−)-Englerin A (EA), a potential novel anti-cancer drug, is a potent selective activator of classical transient receptor potential 4 and 5 (TRPC4, TRPC5) channels. As TRPC4 channels are expressed and functional in the lung endothelium, possible side effects such as lung edema formation may arise during its administration. Well-established in vivo rodent models for toxicological testing, however, rapidly degrade this compound to its inactive derivative, englerin B. Therefore, we chose an ex vivo isolated perfused and ventilated murine lung (IPVML) model to detect edema formation due to toxicants, which also reduces the number of incriminating animal experiments required. To evaluate the sensitivity of the IPVML model, short-time (10 min) drops of the pH from 7.4 down to 4.0 were applied, which resulted in linear changes of tidal volumes, wet-to-dry weight ratios and incorporation of FITC-coupled dextran particles from the perfusate. As expected, biological activity of EA was preserved after perfusion in the IPVML model. Concentrations of 50–100 nM EA continuously perfused through the IPVML model did not change tidal volumes and lung weights significantly. Wet-to-dry weight ratios were increased after perfusion of 100 nM EA but permeation of FITC-coupled dextran particles from the perfusate to the lung tissues was not significantly different. Therefore, EA shows little or no significant acute pulmonary toxicity after application of doses expected to activate target ion channels and the IPVML is a sensitive powerful ex vivo model for evaluating acute lung toxicity in accordance with the 3R rules for animal experimentation.
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Item Type: | Article |
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Copyright, Publisher and Additional Information: | © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Anti-cancer drug; Lung edema; Classical transient receptor potential 4 and 5 (TRPC4, TRPC5); Tidal volume; Wet-to-dry weight ratio; FITC–dextran permeation assay |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) Exception P.O. 4050781788 |
Depositing User: | Symplectic Publications |
Date Deposited: | 22 Feb 2022 16:48 |
Last Modified: | 17 Jun 2022 01:13 |
Status: | Published |
Publisher: | Springer |
Identification Number: | 10.1007/s00204-022-03235-z |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:183867 |
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