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Minoxidil Cannot Be Used To Target Lysyl Hydroxylases during Postnatal Mouse Lung Development: A Cautionary Note
Tilman Pfeffer1, Ettore Lignelli1, Hajime Inoue1
1Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany (T.P., E.L., I.M., D.E.S.S., D.M., W.S., R.E.M.); Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany (T.P., E.L., I.M., D.E.S.S., D.M., I.V., S.H., W.S., R.E.M.); Division of Regenerative Medicine, Department of Plastic and Reconstructive Surgery, St. Marianna University School of Medicine, Kawasaki, Japan (H.I.); and Institute of Virology and Cell Biology (H.S., J.B.) and Department of Dermatology (J.B.), University of Lübeck, Lübeck, Germany.
Minoxidil did not inhibit lysyl hydroxylase activity in newborn mouse lungs, failing to impact lung development in a bronchopulmonary dysplasia model. New inhibitors are needed to target lysyl hydroxylation in vivo.
Area of Science:
- Biochemistry
- Developmental Biology
- Pharmacology
Background:
- Lysyl hydroxylases (PLOD1-3) are implicated in stunted lung development in bronchopulmonary dysplasia (BPD).
- Pulmonary oxygen toxicity exacerbates BPD, leading to impaired lung growth.
- Genetic deficiencies in lysyl hydroxylases cause significant mortality or embryonic lethality in mice.
Purpose of the Study:
- To investigate the efficacy of minoxidil in inhibiting lysyl hydroxylase activity in vivo.
- To determine if minoxidil can attenuate lung development abnormalities in an oxygen-induced BPD mouse model.
Main Methods:
- Minoxidil was administered to newborn mice at the maximum tolerated dose (50 mg/kg/day) in an oxygen toxicity-induced BPD model.
- Lung tissue was analyzed for lysine hydroxylation, collagen crosslinking, and lysyl hydroxylase expression.
- Pharmacokinetic analysis assessed minoxidil concentration in neonatal mouse lungs.
Main Results:
- Minoxidil was detected in neonatal mouse lungs but did not affect lysine hydroxylation or collagen crosslinking.
- Lysyl hydroxylase expression and activity remained unchanged in the lungs.
- Minoxidil administration did not alter normal or stunted lung development in the BPD model.
- Pharmacologically active concentrations of minoxidil were not achieved in neonatal lung tissue.
Conclusions:
- Minoxidil is ineffective at inhibiting lysyl hydroxylase activity in vivo at the tested doses.
- Minoxidil cannot be used to pharmacologically target lysyl hydroxylation in neonatal mouse lung development.
- Development of novel, specific lysyl hydroxylase inhibitors is warranted for therapeutic applications.
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