Alveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury
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Authors
LaRiviere, W. B.
Liao, S.
McMurtry, S. A.
Oshima, K.
Han, X.
Zhang, F.
Yan, S.
Haeger, S. M.
Ransom, M.
Bastarache, J. A.
Issue Date
2020-06-01
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Alternative Title
Abstract
The pulmonary epithelial glycocalyx, an anionic cell surface layer enriched in glycosaminoglycans such as heparan sulfate and chondroitin sulfate, contributes to the alveolar barrier. Direct injury to the pulmonary epithelium induces shedding of heparan sulfate into the air space; the impact of this shedding on recovery after lung injury is unknown. Using mass spectrometry, we found that heparan sulfate was shed into the air space for up to 3 wk after intratracheal bleomycin-induced lung injury and coincided with induction of matrix metalloproteinases (MMPs), including MMP2. Delayed inhibition of metalloproteinases, beginning 7 days after bleomycin using the nonspecific MMP inhibitor doxycycline, attenuated heparan sulfate shedding and improved lung function, suggesting that heparan sulfate shedding may impair lung recovery. While we also observed an increase in air space heparanase activity after bleomycin, pharmacological and transgenic inhibition of heparanase in vivo failed to attenuate heparan sulfate shedding or protect against bleomycin-induced lung injury. However, experimental augmentation of airway heparanase activity significantly worsened post-bleomycin outcomes, confirming the importance of epithelial glycocalyx integrity to lung recovery. We hypothesized that MMP-associated heparan sulfate shedding contributed to delayed lung recovery, in part, by the release of large, highly sulfated fragments that sequestered lung-reparative growth factors such as hepatocyte growth factor. In vitro, heparan sulfate bound hepatocyte growth factor and attenuated growth factor signaling, suggesting that heparan sulfate shed into the air space after injury may directly impair lung repair. Accordingly, administration of exogenous heparan sulfate to mice after bleomycin injury increased the likelihood of death due to severe lung dysfunction. Together, our findings demonstrate that alveolar epithelial heparan sulfate shedding impedes lung recovery after bleomycin.
Description
American Journal of Physiology-Lung Cellular and Molecular Physiology, 318, L1198–L1210
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Full Citation
Alveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury, W. LaRiviere, S. Liao, S. McMurtry, K. Oshima, X. Han, F. Zhang, S. Yan, S. Haeger, M. Ransom, J. Bastarache, R. J. Linhardt, E. Schmidt, Y. Yang, American Journal of Physiology-Lung Cellular and Molecular Physiology, 318, L1198–L1210, 2020.
Publisher
Terms of Use
Journal
Volume
Issue
PubMed ID
DOI
ISSN
15221504
10400605
10400605