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Damage to the Alveolar Epithelial Glycocalyx Contributes to Lung Injury in ARDS

Key findings

  • Pulmonary surfactant is separated from the alveolar epithelium by an epithelial glycocalyx, a layer of glycosaminoglycans
  • In this study, airspace fluid was noninvasively collected from 153 mechanically ventilated patients and analyzed with mass spectrometry to determine whether surfactant function is dependent on the integrity of the alveolar epithelial glycocalyx
  • Increased airspace glycosaminoglycan shedding, an index of glycocalyx degradation, was predominantly associated with male sex and direct lung injury
  • Glycocalyx degradation correlated with the severity and duration of acute respiratory distress syndrome (degree of hypoxemia, days of mechanical ventilation, ICU length of stay, and hospital length of stay)
  • A rapid colorimetric quantification of airspace glycosaminoglycans appeared to be feasible for providing point-of-care prognostic information in routine practice

Direct lung injury is thought to cause acute respiratory distress syndrome (ARDS) by damaging the alveolar epithelium and key supporting structures, including pulmonary surfactant, which lines the alveolar airspace and prevents alveolar collapse during tidal breathing.

Surfactant is separated from the alveolar epithelium by an epithelial glycocalyx, a layer of glycosaminoglycans. The glycocalyx was recognized more than 50 years ago but is understudied, largely because of the infeasibility of obtaining bronchoalveolar lavage from critically ill patients.

Using a novel noninvasive methodology, Alicia N. Rizzo, MD, PhD, a research fellow in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, Eric P. Schmidt, MD, chief of the Division, and colleagues determined that degradation of the alveolar epithelial glycocalyx contributes to ARDS pathophysiology. They report a novel diagnostic and the therapeutic implications of their findings in JCI Insight.


The researchers collected airspace fluid from heat and moisture exchanger filters—bacteriostatic sponges routinely used in the care of mechanically ventilated patients. The contents of heat and moisture exchanger fluid (HMEF) closely approximate the contents of directly aspirated pulmonary edema fluid.

153 mechanically ventilated patients were prospectively studied for clinical factors associated with glycosaminoglycan shedding into HMEF, an index of glycocalyx degradation. The study population included:

  • 66 participants with ARDS per the 2012 Berlin Definition
  • 6 participants with cardiogenic pulmonary edema
  • 16 participants classified as having "mixed" cardiogenic and noncardiogenic pulmonary edema
  • 21 participants intubated for airway protection in the absence of lung disease
  • 44 participants with respiratory failure due to other causes (patients with COVID-19 were excluded for safety reasons)

HMEF was collected within 24 hours after the start of mechanical ventilation, and mass spectrometry was used to detect glycosaminoglycans.


Consistent with the known heterogeneity of ARDS, the researchers observed substantial heterogeneity of airspace glycosaminoglycan shedding:

  • Shedding was increased in patients with ARDS who had risk factors for direct lung injury (pneumonia or aspiration) compared with those who had only risk factors for indirect lung injury (sepsis, pancreatitis, transfusion, or trauma) (P=0.046)
  • Still, shedding was judged low in 56% of patients with direct lung injury, emphasizing that clinical categorization of "direct" and "indirect" lung injury probably oversimplifies the multiple mechanisms that contribute to ARDS
  • Males were more likely than females to be in the high-shedding group (median total glycosaminoglycans, 158 vs. 32 ng/mL; P=0.018)

The quantity of glycosaminoglycan shedding was closely associated with ARDS severity and duration: the degree of hypoxemia at the time of HME filter collection (ρ = −0.51, P=0.0099), total days of mechanical ventilation (ρ=0.31, P=0.013), ICU length of stay (ρ=0.32, P=0.011), and hospital length of stay (ρ=0.30, P=0.017).

Point-of-Care Testing

Because mass spectrometry is expensive and outside the scope of normal hospital practice, the researchers evaluated the predictive value of analyzing HMEF with dimethylmethylene blue (DMMB), a rapid colorimetric assay of sulfated glycosaminoglycans. DMMB and mass spectrometry results were closely correlated (ρ=0.79, P<0.0001).

Additional evidence suggested the assay is sufficiently robust to be used in clinical practice. The researchers analyzed HMEF from filters that were changed during routine care of an additional 24 patients with ARDS, rather than during the standardized protocol used earlier in the study. Glycosaminoglycan shedding quantified by DMMB was increased compared with controls who had pulmonary edema (P<0.05).

Toward Effective Therapy

Decades of clinical trials have largely failed to identify effective pharmacologic strategies for ARDS. A breakthrough could be to develop pharmacologic agents that block glycocalyx degradation or enhance native regeneration mechanisms.

Such drugs would presumably benefit patients who either have risk factors for glycosaminoglycan shedding (male sex and pneumonia/aspiration) or have elevated glycosaminoglycan levels in HMEF as assessed by DMMB.

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