Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 556, Issue -, Pages 199-206Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.03.161
Keywords
Endothelial; Barrier dysfunction; Hemoglobin; Cell death
Categories
Funding
- National Institutes of Health [HL135849, HL103836, HL094296]
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Circulating cell-free hemoglobin (CFH) contributes to endothelial injury in various inflammatory and hemolytic conditions, but does not lead to endothelial barrier dysfunction through cell death mechanisms. Despite causing a decrease in cell viability over time, CFH does not increase apoptosis and cannot be prevented by inhibitors of various cell death pathways, indicating that cell death does not play a role in CFH-mediated lung microvascular endothelial barrier dysfunction.
Circulating cell-free hemoglobin (CFH) contributes to endothelial injury in several inflammatory and hemolytic conditions. We and others have shown that CFH causes increased endothelial permeability, but the precise mechanisms of CFH-mediated endothelial barrier dysfunction are not fully understood. Based on our previous study in a mouse model of sepsis demonstrating that CFH increased apoptosis in the lung, we hypothesized that CFH causes endothelial barrier dysfunction through this cell death mechanism. We first confirmed that CFH causes human lung microvascular barrier dysfunction in vitro that can be prevented by the hemoglobin scavenger, haptoglobin. While CFH caused a small but sig-nificant decrease in cell viability measured by the membrane impermeable DNA dye Draq7 in human lung microvascular endothelial cells, CFH did not increase apoptosis as measured by TUNEL staining or Western blot for cleaved caspase-3. Moreover, inhibitors of apoptosis (Z-VAD-FMK), necrosis (IM-54), necroptosis (necrostatin-1), ferroptosis (ferrostatin-1), or autophagy (3-methyladenine) did not prevent CFH-mediated endothelial barrier dysfunction. We conclude that although CFH may cause a modest decrease in cell viability over time, cell death does not contribute to CFH-mediated lung microvascular endothelial barrier dysfunction . (c) 2021 Elsevier Inc. All rights reserved.
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