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dc.contributor.authorLaRiviere, W. B.
dc.contributor.authorLiao, S.
dc.contributor.authorMcMurtry, S. A.
dc.contributor.authorOshima, K.
dc.contributor.authorHan, X.
dc.contributor.authorZhang, F.
dc.contributor.authorYan, S.
dc.contributor.authorHaeger, S. M.
dc.contributor.authorRansom, M.
dc.contributor.authorBastarache, J. A.
dc.contributor.authorLinhardt, R. J.
dc.contributor.authorSchmidt, E. P.
dc.contributor.authorYang, Y.
dc.date2020
dc.date.accessioned2022-06-27T15:41:32Z
dc.date.available2022-06-27T15:41:32Z
dc.date.issued2020-06-01
dc.identifier.citationAlveolar 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.
dc.identifier.issn15221504
dc.identifier.issn10400605
dc.identifier.urihttps://doi.org/10.1152/ajplung.00063.2020
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5500
dc.descriptionAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 318, L1198–L1210
dc.descriptionNote : 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.
dc.description.abstractThe 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.
dc.description.sponsorshipNational Heart, Lung, and Blood Institute
dc.languageen_US
dc.language.isoENG
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleAlveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury
dc.typeArticle
dcterms.isPartOfJournal
dcterms.isVersionOfhttps://doi.org/10.1152/ajplung.00063.2020
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
rpi.description.pagesL1198-L1210
rpi.description.volume318


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