Oxidized Cell-Free Hemoglobin Induces Endothelial and Mitochondrial Dysfunction in the Pulmonary Microvasculature

Abstract

The development of acute respiratory distress syndrome (ARDS) during sepsis is precipitated by breakdown of the alveolar epithelial-capillary endothelial barrier and influx of inflammatory cells into the airspace. Cell free hemoglobin (CFH) is released from red blood cells in high amounts during sepsis and causes injury to the endothelium. CFH may have differential effects based on redox states (CFH2+ and CFH3+). We utilized cell culture of primary human lung microvascular endothelial cells as a model of the pulmonary endothelium. CFH3+ induced barrier dysfunction and increased leukocyte adhesion in pulmonary endothelial cells, two key features of ARDS development. As a potential mechanism of this dysfunction, we saw changes in mitochondrial shape, size, and oxidative respiration. Activation of the mitochondrial permeability transition pore (mPTP) and formation of 8-hydroxy-2'-deoxyguanosine may drive these changes in endothelial and mitochondrial function. Further, CFH3+ induces extracellular vesicle formation in endothelial cells, a potential mechanism of mtDNA release.