Epithelial Heparan Sulfate Contributes to Alveolar Barrier Function and is Shed during Lung Injury

Authors
Haeger, Sarah M.
Liu, Xinyue
Han, Xiaorui
Brennan McNeil, J.
Oshima, Kaori
McMurtry, Sarah A.
Yang, Yimu
Ouyang, Yilan
Zhang, Fuming
Nozik-Grayck, Eva
ORCID
https://orcid.org/0000-0003-2219-5833
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Issue Date
2018-09-01
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Full Citation
Epithelial Heparan Sulfate Contributes to Alveolar Barrier Function and is Shed during Lung Injury, S. M. Haeger, X. Liu, X. Han, J. B. McNeil, K. Oshima, S. A. McMurtry, Y. Yang, Y. Ouyang, F. Zhang, E. Nozik-Grayck, R. L. Zemans, R. M. Tuder, J. A. Bastarache, R. J. Linhardt, E. P. Schmidt, American Journal of Respiratory Cell and Molecular Biology, 59, 363–374, 2018.
Abstract
The lung epithelial glycocalyx is a carbohydrate-enriched layer lining the pulmonary epithelial surface. Although epithelial glycocalyx visualization has been reported, its composition and function remain unknown. Using immunofluorescence and mass spectrometry, we identified heparan sulfate (HS) and chondroitin sulfate within the lung epithelial glycocalyx. In vivo selective enzymatic degradation of epithelial HS, but not chondroitin sulfate, increased lung permeability. Using mass spectrometry and gel electrophoresis approaches to determine the fate of epithelial HS during lung injury, we detected shedding of 20 saccharide-long or greater HS into BAL fluid in intratracheal LPS-treated mice. Furthermore, airspace HS in clinical samples from patients with acute respiratory distress syndrome correlated with indices of alveolar permeability, reflecting the clinical relevance of these findings. The length of HS shed during intratracheal LPS-induced injury (≥20 saccharides) suggests cleavage of the proteoglycan anchoring HS to the epithelial surface, rather than cleavage of HS itself. We used pharmacologic and transgenic animal approaches to determine that matrix metalloproteinases partially mediate HS shedding during intratracheal LPS-induced lung injury. Although there was a trend toward decreased alveolar permeability after treatment with the matrix metalloproteinase inhibitor, doxycycline, this did not reach statistical significance. These studies suggest that epithelial HS contributes to the lung epithelial barrier and its degradation is sufficient to increase lung permeability. The partial reduction of HS shedding achieved with doxycycline is not sufficient to rescue epithelial barrier function during intratracheal LPS-induced lung injury; however, whether complete attenuation of HS shedding is sufficient to rescue epithelial barrier function remains unknown.
Description
American Journal of Respiratory Cell and Molecular Biology, 59, 363–374
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
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The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
American Journal of Respiratory Cell and Molecular Biology
https://harc.rpi.edu/
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