Pengfei Li1, Yue Zhou1,2, Andrew J Goodwin3, James A Cook4, Perry V Halushka5,6, Xian K Zhang7, Carole L Wilson3, Lynn M Schnapp3, Basilia Zingarelli8, Hongkuan Fan1,9. 1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston. 2. Department of Biopharmaceutics, College of Pharmacy, Nanjing University of Chinese Medicine, China. 3. Divisions of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, Charleston. 4. Department of Neurosciences, Medical University of South Carolina, Charleston. 5. Department of Medicine, Medical University of South Carolina, Charleston. 6. Department of Pharmacology, Medical University of South Carolina, Charleston. 7. Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston. 8. Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Ohio. 9. Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston.
Abstract
Background: Pericytes are vascular mural cells and are embedded in the basement membrane of the microvasculature. Recent studies suggest a role for pericytes in lipopolysaccharide (LPS)-induced microvascular dysfunction and mortality, but the mechanisms of pericyte loss in sepsis are largely unknown. Methods: By using a cecal ligation and puncture (CLP)-induced murine model of sepsis, we observed that CLP led to lung and renal pericyte loss and reduced lung pericyte density and pericyte/endothelial cell (EC) coverage. Results: Up-regulated Friend leukemia virus integration 1 (Fli-1) messenger ribonucleic acid (RNA) and protein levels were found in lung pericytes from CLP mice in vivo and in LPS-stimulated lung pericytes in vitro. Knockout of Fli-1 in Foxd1-derived pericytes prevented CLP-induced pericyte loss, vascular leak, and improved survival. Disrupted Fli-1 expression by small interfering RNA inhibited LPS-induced inflammatory cytokines and chemokines in cultured lung pericytes. Furthermore, CLP-induced pericyte pyroptosis was mitigated in pericyte Fli-1 knockout mice. Conclusions: Our findings suggest that Fli-1 is a potential therapeutic target in sepsis.
Background: Pericytes are vascular mural cells and are embedded in the basement membrane of the microvasculature. Recent studies suggest a role for pericytes in lipopolysaccharide (LPS)-induced microvascular dysfunction and mortality, but the mechanisms of pericyte loss in sepsis are largely unknown. Methods: By using a cecal ligation and puncture (CLP)-induced murine model of sepsis, we observed that CLP led to lung and renal pericyte loss and reduced lung pericyte density and pericyte/endothelial cell (EC) coverage. Results: Up-regulated Friend leukemia virus integration 1 (Fli-1) messenger ribonucleic acid (RNA) and protein levels were found in lung pericytes from CLPmice in vivo and in LPS-stimulated lung pericytes in vitro. Knockout of Fli-1 in Foxd1-derived pericytes prevented CLP-induced pericyte loss, vascular leak, and improved survival. Disrupted Fli-1 expression by small interfering RNA inhibited LPS-induced inflammatory cytokines and chemokines in cultured lung pericytes. Furthermore, CLP-induced pericyte pyroptosis was mitigated in pericyte Fli-1 knockout mice. Conclusions: Our findings suggest that Fli-1 is a potential therapeutic target in sepsis.
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