Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome

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Abstract

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding, which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.

Authors

Alicia N. Rizzo, Sarah M. Haeger, Kaori Oshima, Yimu Yang, Alison M. Wallbank, Ying Jin, Marie Lettau, Lynda A. McCaig, Nancy E. Wickersham, J. Brennan McNeil, Igor Zakharevich, Sarah A. McMurtry, Christophe J. Langouët-Astrié, Katrina W. Kopf, Dennis R. Voelker, Kirk C. Hansen, Ciara M. Shaver, V. Eric Kerchberger, Ryan A. Peterson, Wolfgang M. Kuebler, Matthias Ochs, Ruud A.W. Veldhuizen, Bradford J. Smith, Lorraine B. Ware, Julie A. Bastarache, Eric P. Schmidt