1. Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis
- Author
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Han Noo Ri Lee, Lorraine B. Ware, Julie A. Bastarache, Tatiana N. Sidorova, Jamie E. Meegan, Colleen M. Brophy, James L. Wynn, Nathan D. Putz, J. Brennan McNeil, Stuart R. Landstreet, Joyce Cheung-Flynn, Padmini Komalavilas, Ciara M. Shaver, and Jordan J. Jesse
- Subjects
0301 basic medicine ,Physiology ,Respiratory System ,Vascular permeability ,Apoptosis ,030204 cardiovascular system & hematology ,Pathology and Laboratory Medicine ,Biochemistry ,Diagnostic Radiology ,Pathogenesis ,Hemoglobins ,Mice ,0302 clinical medicine ,Immune Physiology ,Medicine and Health Sciences ,Lung ,Immune Response ,Innate Immune System ,Multidisciplinary ,Cell Death ,Radiology and Imaging ,Endogenous mediator ,Pulmonary Imaging ,3. Good health ,medicine.anatomical_structure ,Cell Processes ,Physical Sciences ,Medicine ,Cytokines ,Female ,medicine.symptom ,Anatomy ,Research Article ,Imaging Techniques ,Science ,Immunology ,Materials Science ,Material Properties ,Inflammation ,Research and Analysis Methods ,Permeability ,Proinflammatory cytokine ,Sepsis ,Capillary Permeability ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,medicine ,Animals ,Humans ,Hemoglobin ,business.industry ,Organ dysfunction ,Endothelial Cells ,Biology and Life Sciences ,Proteins ,Cell Biology ,Molecular Development ,medicine.disease ,eye diseases ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Immune System ,Lungs ,business ,Developmental Biology - Abstract
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.
- Published
- 2019