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Am J Pathol. 2016 Feb;186(2):248-58. doi: 10.1016/j.ajpath.2015.10.001. Epub 2015 Dec 10.

Exocytosis of Endothelial Lysosome-Related Organelles Hair-Triggers a Patchy Loss of Glycocalyx at the Onset of Sepsis.

Author information

1
Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York.
2
Department of Biomedical Engineering, The City College of the City University of New York, New York, New York.
3
Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York; Department of Anesthesiology, Ulsan Medical College, Seoul, Republic of Korea.
4
Department of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York. Electronic address: michael_goligorsky@nymc.edu.
5
Department of Biomedical Engineering, The City College of the City University of New York, New York, New York. Electronic address: fu@ccny.cuny.edu.

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.

PMID:
26683662
PMCID:
PMC4729233
DOI:
10.1016/j.ajpath.2015.10.001
[Indexed for MEDLINE]
Free PMC Article

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