The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis
- 22 July 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 18 (8), 1217-1223
- https://doi.org/10.1038/nm.2843
Abstract
The glycocalyx is a layer of proteoglycans and complex carbohydrates that lines the endothelial cell surface in blood vessels. Schmidt et al. show that in mouse models of sepsis, lung inflammation and injury depend on glycocalyx degradation, which increases neutrophil access to endothelial adhesion molecules. The authors also provide data indicating the potential relevance of this mechanism of lung injury to humans with sepsis. 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.Keywords
This publication has 54 references indexed in Scilit:
- The neutrophil in vascular inflammationNature Medicine, 2011
- Two distinct aquaporin-4 cDNAs isolated from medullary cone of quail kidneyComparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2007
- Structural and functional characteristics of lung macro- and microvascular endothelial cell phenotypesMicrovascular Research, 2004
- Endothelial Cell Glycocalyx Modulates Immobilization of Leukocytes at the Endothelial SurfaceArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Near-Wall μ-PIV Reveals a Hydrodynamically Relevant Endothelial Surface Layer in Venules In VivoBiophysical Journal, 2003
- Tumor Necrosis Factor-α Induces Early-Onset Endothelial Adhesivity by Protein Kinase Cζ–Dependent Activation of Intercellular Adhesion Molecule-1Circulation Research, 2003
- The immunopathogenesis of sepsisNature, 2002
- Role of glycocalyx in leukocyte-endothelial cell adhesionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2002
- The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitroBritish Journal of Pharmacology, 2000
- Permeability of frog mesenteric capillaries after partial pronase digestion of the endothelial glycocalyx.Journal Of Physiology-London, 1990