期刊
ARCHIVES OF TOXICOLOGY
卷 96, 期 4, 页码 1055-1063出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-022-03235-z
关键词
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
类别
资金
- Projekt DEAL
- Deutsche Forschungsgemeinschaft (DFG, Research Training Group GRK 2338)
This study used an ex vivo murine lung model to evaluate the toxic effects of (-)-Englerin A (EA) in causing lung edema. The results showed that EA had little or no acute pulmonary toxicity at doses expected to activate target ion channels. Therefore, the ex vivo isolated perfused and ventilated murine lung model is a sensitive and powerful method for evaluating acute lung toxicity.
(-)-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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