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

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 5

Alveolar epithelial glycocalyx degradation impairs surfactant function.

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Alveolar epithelial glycocalyx degradation impairs surfactant function. ...
(A) The effect of Hep-I/III treatment on the quantity of total surfactant (TS) and its subfractions, the surface-active large aggregates (LA) and the inactive small aggregates (SA). (B) The minimum surface tension of the LA surfactant subfraction from Hep-I/III–treated mice compared with HI Hep-I/III–treated controls. n = 5 mice per group. *P < 0.05 by 2-tailed unpaired t test. Data are represented as mean ± SEM. (C–H) In both HI Hep-I/III–treated (C) and Hep-I/III–treated (D–H) animals, transmission electron microscopy revealed a thin layer of electron-dense alveolar liquid film (open arrowheads) containing lipid fragments on top of the alveolar epithelium. This film had an increased thickness in Hep-I/III–treated mice (D). Higher amounts were particularly found in alveolar corners and interalveolar pores of Kohn or covering the secretory surface of type II alveolar epithelial cells (AECII; C, D, G, and H). Alveolar liquid–filled infoldings of the alveolar epithelium (asterisk) were present to a larger extent in the Hep-I/III–treated mice (E). In Hep-I/III–treated mice, intra-alveolar surfactant subtypes, in particular freshly secreted lamellar body–like forms (LBL) in close proximity to tubular myelin (TM) at the air-liquid interface, were more abundant (F). The electron density of the liquid film and the quantity of contained small lipid fragments were increased in the Hep-I/III group (G). Lamellar lipid accumulations were also found in some alveolar macrophages (AM; H) and capillaries (arrows; D and G). alv, alveolar lumen; cap, capillary lumen. Scale bars: 1 μm. (I) The relationship between GAG shedding and surfactant protein D in HMEF. Gray box represents values at or below the lower limit of detection (variability of this limit reflects different sample dilutions). n = 115 participants with respiratory failure. Spearman ρ and P values were calculated as indicated.