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Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis.

Meegan JE, Shaver CM, Putz ND, Jesse JJ, Landstreet SR, Lee HNR, Sidorova TN, McNeil JB, Wynn JL, Cheung-Flynn J, Komalavilas P, Brophy CM, Ware LB, Bastarache JA
PLoS One. 2020 15 (2): e0228727

PMID: 32012200 · PMCID: PMC6996826 · DOI:10.1371/journal.pone.0228727

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.

MeSH Terms (13)

Animals Apoptosis Capillary Permeability Endothelial Cells Female Hemoglobins Humans Inflammation Lung Mice Mice, Inbred C57BL Oxidative Stress Sepsis

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