Alveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury
| Autor: | Sarah M. Haeger, Yimu Yang, Kaori Oshima, Xiaorui Han, S. Liao, S Yan, Robert J. Linhardt, M Ransom, Fuming Zhang, Wells B. LaRivière, Eric P. Schmidt, Julie A. Bastarache, Sarah A. McMurtry |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Physiology Lung injury Bleomycin Cell Line 03 medical and health sciences chemistry.chemical_compound Sulfation Risk Factors Physiology (medical) medicine Animals Heparanase Chondroitin sulfate Glucuronidase Lung 030102 biochemistry & molecular biology Lung Injury Cell Biology Heparan sulfate respiratory system Matrix Metalloproteinases Respiratory Function Tests Up-Regulation respiratory tract diseases Cell biology Mice Inbred C57BL Pulmonary Alveoli carbohydrates (lipids) 030104 developmental biology medicine.anatomical_structure chemistry Respiratory Mechanics Intercellular Signaling Peptides and Proteins Hepatocyte growth factor Heparitin Sulfate Signal Transduction Research Article medicine.drug |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00063.2020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|