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Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome
Alicia N. Rizzo, … , Julie A. Bastarache, Eric P. Schmidt
Alicia N. Rizzo, … , Julie A. Bastarache, Eric P. Schmidt
Published December 7, 2021
Citation Information: JCI Insight. 2022;7(2):e154573. https://doi.org/10.1172/jci.insight.154573.
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Research Article Pulmonology

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

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Figure 1

GAG shedding is heterogeneous in ARDS.

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GAG shedding is heterogeneous in ARDS.
(A) Graphical representation (not...
(A) Graphical representation (not to scale) of the alveolar epithelial glycocalyx, a layer of GAGs — heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) — that lines the apical alveolar epithelial surface. In murine models of acute lung injury, the glycocalyx is damaged, leading to shedding of GAGs into the airspace fluid. (B) Graphical representation of a patient on a ventilator circuit containing a heat and moisture exchanger (HME) filter, from which airspace fluid can be noninvasively sampled in mechanically ventilated patients. (C) Assessment of airspace fluid GAG shedding in mechanically ventilated patients was performed by mass spectrometry analysis of HMEF. (D) Partitioning around k-medoids clustering using the variables HS, CS, and HA was performed to group patients into high, medium, and low shedding clusters based on the degree of GAG shedding. (E) Assessment of the effect of patients’ sex on airspace GAG levels in patients with respiratory failure. n = 153 participants with respiratory failure. *P < 0.05 by Wilcoxon’s rank sum test. Data are represented as median and IQR with individual data points for those outside of 1.5 × IQR. A and B were created with BioRender (biorender.com).

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