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

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

doi:10.1172/jci.insight.154573

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.

Highlights

Acute Respiratory Distress Syndrome (ARDS) is a common cause of acute respiratory failure with substantial morbidity and mortality [1]
In contrast to bronchoalveolar lavage (BAL), airspace fluid can be collected noninvasively from mechanicallyventilated ARDS patients using heat moisture exchanger (HME) filters, bacteriostatic sponges that are routinely used in the care of mechanically ventilated patients (Figure 1B)
Our “bedside-to-bench” study demonstrates that alveolar epithelial glycocalyx integrity is critical to surfactant function, and that shedding of this layer is associated with the duration of respiratory failure in patients with ARDS and all cause respiratory failure

Summary

Introduction

Acute Respiratory Distress Syndrome (ARDS) is a common cause of acute respiratory failure with substantial morbidity and mortality [1]. Despite promising pre-clinical data, decades of clinical trials have been largely unsuccessful in identifying effective pharmacologic strategies [2]. This disconnect has been increasingly attributed to mechanistic heterogeneity underlying this complex syndrome, inspiring efforts to identify ARDS sub-phenotypes which may impart differential responses to pharmacologic agents [3, 4]. One commonly recognized determinant of ARDS heterogeneity is the route of the ARDS-triggering injury, differentiated between inhaled insults (“direct lung injury”, such as pneumonia or aspiration) and bloodstream-initiated pulmonary insults (“indirect lung injury”, such as sepsis or pancreatitis) [5]. Despite the intuitive differences between these forms of ARDS, their mechanistic underpinnings are not well understood, and these crude classifications likely oversimplify complex underlying pathophysiology. A thorough understanding of the patient-level factors and mechanisms driving

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Conclusion