The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis

Eric P. Schmidt, Yimu Yang, William J. Janssen, Aneta Gandjeva, Mario J. Perez, Lea Barthel, Rachel L. Zemans, Joel C. Bowman, Dan E. Koyanagi, Zulma X. Yunt, Lynelle P. Smith, Sara S. Cheng, Katherine H. Overdier, Kathy R. Thompson, Mark W. Geraci, Ivor S. Douglas, David B. Pearse, Rubin M. Tuder

Research output: Contribution to journalArticle

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-Î ± (TNF-Î ±)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-Î ±g-responsive, heparan sulfateg-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.

Original languageEnglish (US)
Pages (from-to)1217-1223
Number of pages7
JournalNature medicine
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis'. Together they form a unique fingerprint.

  • Cite this

    Schmidt, E. P., Yang, Y., Janssen, W. J., Gandjeva, A., Perez, M. J., Barthel, L., Zemans, R. L., Bowman, J. C., Koyanagi, D. E., Yunt, Z. X., Smith, L. P., Cheng, S. S., Overdier, K. H., Thompson, K. R., Geraci, M. W., Douglas, I. S., Pearse, D. B., & Tuder, R. M. (2012). The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nature medicine, 18(8), 1217-1223. https://doi.org/10.1038/nm.2843