1. Modulation of the Permeability-Inducing Factor Angiopoietin-2 Through Bifonazole in Systemic Inflammation.
- Author
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Pape T, Idowu TO, Etzrodt VM, Stahl K, Seeliger B, Haller H, and David S
- Subjects
- Cells, Cultured, Endothelial Cells, Humans, Angiopoietin-2 physiology, Antifungal Agents pharmacology, Capillary Permeability drug effects, Imidazoles pharmacology, Inflammation physiopathology
- Abstract
Background: Vascular barrier breakdown in sepsis represents a key component of the maladaptive host response to infection and the release of endothelial Angiopoietin-2 (Angpt-2) is a mechanistic driver of endothelial hyperpermeability. Angpt-2 is associated with morbidity and mortality but a targeted therapeutic approach is not available. We screened for U.S. Food and Drug Administration (FDA) approved drugs that might have off-target effects decreasing Angpt-2 and therefore, ameliorating capillary leakage., Methods: Endothelial cells were isolated from human umbilical veins (HUVECs) and used for in vitro studies at baseline and after stimulation (FDA-library screening, RT-PCR, ELISA, immunocytochemistry, MTT assay). On the functional level, we assessed real-time transendothelial electrical resistance (TER) using an electric cell-substrate impedance sensing device., Results: We found that the anti-fungal Bifonazole (BIFO) reduces spontaneous Angpt-2 release in a time- and dose-dependent manner after 8, 12, and 24 h (24 h: veh: 15.6 ± 0.7 vs. BIFO: 8.6 ± 0.8 ng/mL, P < 0.0001). Furthermore, we observed a reduction in its intra-cellular content by 33% (P < 0.001). Stimulation with tumor necrosis factor α induced a strong release of Angpt-2 that could analogously be blocked by additional treatment with BIFO (veh: 1.58 ± 0.2 vs. BIFO: 1.02 ± 0.1, P < 0.0001). Quantification of endothelial permeability by TER revealed that BIFO was sufficient to reduce Thrombin-induced barrier breakdown (veh: 0.82 ± 0.1 vs. BIFO: 1.01 ± 0.02, P < 0.05)., Conclusion: The antifungal BIFO reduces both release and biosynthesis of the endothelial-destabilizing factor Angpt-2 in vitro thereby improving vascular barrier function. Additional studies are needed to further investigate the underlying mechanism and to translate these findings to in vivo models., Competing Interests: The authors report no conflicts of interests., (Copyright © 2021 by the Shock Society.)
- Published
- 2021
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