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Alveolar Epithelial Heparan Sulfate and Chondroitin Sulfate in the Healthy and Injured Lung
Başlık:
Alveolar Epithelial Heparan Sulfate and Chondroitin Sulfate in the Healthy and Injured Lung
Yazar:
Haeger, Sarah Marie, author.
ISBN:
9780438002999
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (150 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Rubin M. Tuder; Eric P. Schmidt Committee members: Christopher M. Evans; Anthony N. Gerber; Arthur Gutierrez-Hartmann; Peter M. Henson; Mary Weiser-Evans.
Özet:
The lung epithelial glycocalyx is a carbohydrate-enriched layer lining the pulmonary epithelial surface. Although epithelial glycocalyx visualization has been reported in vivo, its composition and function remain unknown. Furthermore, while sulfated glycosaminoglycans (GAGs), including heparan sulfate (HS) and chondroitin sulfate (CS), are known to critically contribute to the structure and function of the glycocalyx of numerous cell types, the contribution of HS and CS to the lung epithelial glycocalyx and its function has not been studied.
Disruption of the cell glycocalyx can occur during tissue inflammation and injury. In vitro and in vivo models of lung epithelial injury have demonstrated shedding of the heparan sulfate and chondroitin sulfate proteoglycans syndecan-1 and syndecan-4; however, the release of epithelial HS and CS, and its effect on lung injury and repair has not been studied. In this dissertation a variety of approaches were utilized to determine the existence, structure, and function of alveolar epithelial HS and CS in the healthy lung, to identify and elucidate the mechanism of epithelial HS and CS shedding during intratracheal-induced lung injury in mice and in patients with the acute respiratory distress syndrome (ARDS), and to determine the effect of soluble HS and CS on lung injury and repair during intratracheal-induced lung injury in mice.
Using immunofluorescence and mass spectrometry, we identified heparan sulfate (HS) and chondroitin sulfate (CS) within the lung epithelial glycocalyx. In vivo selective enzymatic degradation of epithelial HS, but not CS, increased baseline lung permeability. Using mass spectrometry and gel electrophoresis approaches to determine the fate of epithelial HS and CS during lung injury, we detected shedding of ≥ 20 saccharide-long HS and CS into bronchoalveolar lavage fluid in intratracheal LPS-treated mice. Further, airspace HS and CS in clinical samples from acute respiratory distress syndrome patients correlated with indices of alveolar permeability, reflecting the translational relevance of these findings. Using pharmacologic and transgenic animal approaches, we determined that matrix metalloproteinases (MMPs) partially mediate HS shedding during intratracheal LPS-induced lung injury. We found a trend towards decreased alveolar permeability after treatment with the MMP inhibitor doxycycline; however, this did not reach statistical significance. HS shed into the alveolar airspace during lung injury was discovered to be heavily un-sulfated, while shed alveolar CS was enriched in 4-O sulfation. As sulfation is essential for most HS functions, it is unlikely that alveolar HS binds other mediators, and as such, may have no effect on lung injury development or subsequent repair. In contrast, we discovered that exogenous 4-O sulfated CS (CS-A) can induce mild inflammation itself and enhance LPS-induced alveolar inflammation, indicating that alveolar 4-O sulfated CS may contribute to alveolar inflammation during injury.
These studies suggest that epithelial HS contributes to the lung epithelial barrier and its degradation is sufficient to increase lung permeability. Furthermore, shedding of epithelial HS and CS into the alveolar airspace occurs during lung injury and correlates with alveolar permeability. While alveolar HS may have no effect on lung injury or repair, alveolar CS may enhance alveolar inflammation during lung injury.
Notlar:
School code: 1639
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680121.1) | 680121-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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