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Micafungin-Induced Suicidal Erythrocyte Death
Thomas Peter1, Rosi Bissinger, Elena Signoretto
1Departments of Cardiology, Cardiovascular Medicine and Physiology, Eberhard-Karls-University of Tuebingen, Tuebingen, Germany.
Background/Aims:
The antifungal drug Micafungin is used for the treatment of diverse fungal infections including candidiasis and aspergillosis. Side effects of Micafungin treatment include microangiopathic hemolytic anemia and thrombocytopenia with microvascular thrombosis. The development of thrombosis may be fostered by stimulation of eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated protein kinase C (PKC), casein kinase 1α or p38 kinase and activated caspases. The present study explored, whether Micafungin induces eryptosis.
Methods:
Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Hemolysis was quantified by measuring haemoglobin concentration in the supernatant.
Results:
A 48 hours exposure of human erythrocytes to Micafungin (10 - 25 µg/ml) significantly increased hemolysis and the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Micafungin (25 µg/ml) did not significantly modify Fluo3-fluorescence, DCFDA fluorescence, or ceramide abundance. The effect of Micafungin on annexin-V-binding was not significantly modified by removal of extracellular Ca2+, by PKC inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase 1α inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM).
Conclusions:
Micafungin triggers hemolysis and eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane.
Insights
The antifungal drug Micafungin triggers red blood cell death (eryptosis) and hemolysis. This process involves cell shrinkage and membrane changes, potentially contributing to thrombosis side effects.
Area of Science:
- Hematology
- Pharmacology
- Cell Biology
Background:
- Micafungin is an antifungal medication used for candidiasis and aspergillosis.
- Side effects include hemolytic anemia and thrombosis, possibly linked to eryptosis (erythrocyte suicidal death).
- Eryptosis is induced by increased calcium, oxidative stress, ceramide, kinases, and caspases.
Purpose of the Study:
- To investigate if Micafungin induces eryptosis in human erythrocytes.
Main Methods:
- Flow cytometry assessed phosphatidylserine externalization, cell volume, intracellular calcium, reactive oxygen species (ROS), and ceramide.
- Hemolysis was measured by hemoglobin in the supernatant.
Main Results:
- Micafungin (10-25 µg/ml) increased hemolysis and phosphatidylserine binding, decreasing cell volume.
- Micafungin did not significantly alter intracellular calcium, ROS, or ceramide levels.
- Inhibitors of PKC, p38, casein kinase 1α, and caspases did not affect Micafungin-induced phosphatidylserine binding.
Conclusions:
- Micafungin induces erythrocyte hemolysis and eryptosis.
- Eryptosis is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte membrane.
