title: Exocytosis of Endothelial Lysosome-Related Organelles Hair-Triggers a Patchy Loss of Glycocalyx at the Onset of Sepsis.
abstract: Sepsis is a systemic inflammatory syndrome induced by bacterial infection that can lead to multiorgan failure. Endothelial surface glycocalyx (ESG) decorating the inner wall of blood vessels is a regulator of multiple vascular functions. Here, we tested a hypothesis that patchy degradation of ESG occurs early in sepsis and is a result of exocytosis of lysosome-related organelles. Time-lapse video microscopy revealed that exocytosis of Weibel-Palade bodies and secretory lysosomes occurred a few minutes after application of lipopolysaccharides to endothelial cells. Two therapeutic maneuvers, a nitric oxide intermediate, NG-hydroxy-l-arginine, and culture media conditioned by endothelial progenitor cells reduced the motility of lysosome-related organelles. Confocal and stochastic optical reconstruction microscopy confirmed the patchy loss of ESG simultaneously with the exocytosis of lysosome-related organelles and Weibel-Palade bodies in cultured endothelial cells and mouse aorta. The loss of ESG was blunted by pretreatment with NG-hydroxy-l-arginine or culture media conditioned by endothelial progenitor cells. Moreover, these treatments resulted in a significant reduction in deaths of septic mice. Our data support the hypothesis assigning to stress-induced exocytosis of these organelles the role of a hair-trigger for local degradation of ESG that initiates leukocyte infiltration, increase in vascular permeability, and partially accounts for the later rates of morbidity and mortality.
authors.affiliation: Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Zullo
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
authors.forename: Tala T
authors.initials: TT
authors.lastname: Azar
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
authors.forename: Wanyi
authors.initials: W
authors.lastname: Yen
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
authors.forename: Min
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Ratliff
authors.affiliation: Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York; Department of Anesthesiology, Ulsan Medical College, Seoul, Republic of Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
authors.forename: John M
authors.initials: JM
authors.lastname: Tarbell
authors.affiliation: Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York. Electronic address: michael_goligorsky@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, New York. Electronic address: fu@ccny.cuny.edu.
authors.forename: Bingmei M
authors.initials: BM
authors.lastname: Fu
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects*; D019276:Glycocalyx / Q000378:metabolism*; D006197:Hair / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D052250:Nitric Oxide Synthase Type III