Abstract
Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Lung Injury / etiology
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Acute Lung Injury / physiopathology*
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Acute Lung Injury / prevention & control
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Adoptive Transfer
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Animals
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Cell Adhesion / physiology
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Disease Models, Animal
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Endothelium / enzymology
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Endothelium / physiology
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Endotoxemia / complications*
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Endotoxemia / physiopathology
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Enzyme Activation
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Gene Expression Regulation / drug effects
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Glucuronidase / analysis
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Glucuronidase / deficiency
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Glucuronidase / physiology
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Glycocalyx / physiology*
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Heparitin Sulfate / antagonists & inhibitors
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Heparitin Sulfate / metabolism
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Humans
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Intestinal Perforation / complications
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Intestinal Perforation / microbiology
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Lipopolysaccharides / toxicity
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Lung / physiopathology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / physiology*
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Pulmonary Alveoli / enzymology
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Pulmonary Alveoli / pathology
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Receptors, Tumor Necrosis Factor, Type I / deficiency
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Receptors, Tumor Necrosis Factor, Type I / physiology
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Respiratory Insufficiency / enzymology
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Respiratory Insufficiency / pathology
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Tumor Necrosis Factor-alpha / physiology
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Ventilator-Induced Lung Injury / enzymology
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Ventilator-Induced Lung Injury / pathology
Substances
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Lipopolysaccharides
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Receptors, Tumor Necrosis Factor, Type I
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
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lipopolysaccharide, E coli O55-B5
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Intercellular Adhesion Molecule-1
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Heparitin Sulfate
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heparanase
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Glucuronidase