title: The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.
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.
authors: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Program in Translational Lung Research, University of Colorado School of Medicine, Aurora, Colorado, USA; Denver Health Medical Center, Denver, Colorado, USA. eric.schmidt@ucdenver.edu
authors: Eric P
authors: EP
authors: Schmidt
authors: Yimu
authors: Y
authors: Yang
authors: William J
authors: WJ
authors: Janssen
authors: Aneta
authors: A
authors: Gandjeva
authors: Mario J
authors: MJ
authors: Perez
authors: Lea
authors: L
authors: Barthel
authors: Rachel L
authors: RL
authors: Zemans
authors: Joel C
authors: JC
authors: Bowman
authors: Dan E
authors: DE
authors: Koyanagi
authors: Zulma X
authors: ZX
authors: Yunt
authors: Lynelle P
authors: LP
authors: Smith
authors: Sara S
authors: SS
authors: Cheng
authors: Katherine H
authors: KH
authors: Overdier
authors: Kathy R
authors: KR
authors: Thompson
authors: Mark W
authors: MW
authors: Geraci
authors: Ivor S
authors: IS
authors: Douglas
authors: David B
authors: DB
authors: Pearse
authors: Rubin M
authors: RM
authors: Tuder
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D019264:Adoptive Transfer; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D004195:Disease Models, Animal; D004727:Endothelium / Q000201:enzymology / Q000502:physiology; D019446:Endotoxemia / Q000150:complications* / Q000503:physiopathology; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000032:analysis / Q000172:deficiency / Q000502:physiology; D019276:Glycocalyx / Q000502:physiology*; D006497:Heparan Sulfate / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007416:Intestinal Perforation / Q000150:complications / Q000382:microbiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000502:physiology; D012131:Respiratory Insufficiency / Q000201:enzymology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000473:pathology; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D018799:Intercellular Adhesion Molecule-1; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase; C506236:Tnfrsf1a protein, mouse; C482199:lipopolysaccharide, E coli O55-B5