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.

N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19

“…After exposure to an infectious pathogen or inflammatory insult, alteration in the composition of the GL is one of the earliest features during sepsis [ 65 , 68 ]. Following infection, acute injury, or inflammatory conditions, glucuronidases, such as heparanases (HPSEs) [ 58 , 66 , 79 ], reactive oxygen species (ROS) [ 65 ], and other proteases [ 5 , 80 , 81 ], cause shedding of HS and PGs [ 25 , 57 , 82 ]. Subsequently, adhesion molecules such as E-selectin and intercellular adhesion molecules are exposed on the denuded endothelium [ 6 , 40 , 80 , 83 ], which result in accelerated inflammation [ 84 ], vascular permeability [ 58 , 85 ], oedema, platelet aggregation, hypercoagulation, and a loss of vascular responsiveness [ 3 , 40 , 65 , 68 , 86 , 87 ].…”

“…It contributes to neutrophil adhesion, leading to diffuse alveolar damage, interstitial lung oedema, and clot formation during acute lung injury in sepsis and ARDS [ 61 , 68 , 78 ]. There exists a clear association between alveolar epithelial and endothelial GL shedding and the establishment of ARDS [ 81 , 82 ] and COVID-19 [ 4 ]. Moreover, circulating HS fragments are capable of influencing growth factors and other signaling pathways distant to the site of GL injury, which explains the systemic (i.e.…”

Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood

“…More specifically, we found that plasma levels of markers of endothelial glycocalyx degradation (syndecan and heparan sulfate fragments), heparan sulfate proteoglycan cleaving enzymes (heparanase and MMP2), and endothelial activation (vWF and thrombomodulin) are elevated in MCD. Rizzo et al also demonstrated that glycocalyx degradation in the lung is associated with Article surfactant release to the circulation (Rizzo et al, 2022). Based on these observations, endothelial dysfunction in MCD could act as a mechanism favoring the release to the circulation of surfactants from active respiratory tract infections as well as facilitate the interaction of high molecular weight surfactants with podocyte SIRPa.…”

New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome

“…Recent data reveal important roles for the alveolar epithelial glycocalyx in lung injury pathogenesis. The glycocalyx regulates cellular barrier function and cell adhesion (reviewed in [ 10 ]), and glycocalyx shedding can mediate lung disease [ 70 , 71 , 72 , 73 ]. In patients with ARDS, glycosaminoglycan accumulation in respiratory specimens, likely a marker of glycocalyx proteoglycan shedding, correlates with alveolar barrier permeability indices, duration of mechanical ventilation, and matrix metalloproteinase 7 (MMP-7) levels [ 72 , 73 ].…”

“…The glycocalyx regulates cellular barrier function and cell adhesion (reviewed in [ 10 ]), and glycocalyx shedding can mediate lung disease [ 70 , 71 , 72 , 73 ]. In patients with ARDS, glycosaminoglycan accumulation in respiratory specimens, likely a marker of glycocalyx proteoglycan shedding, correlates with alveolar barrier permeability indices, duration of mechanical ventilation, and matrix metalloproteinase 7 (MMP-7) levels [ 72 , 73 ]. MMP-7, via shedding of syndecan-1, a proteoglycan prominently expressed by the lung epithelium, promotes alveolar airspace neutrophil recruitment and activation after various injuries [ 74 , 75 ].…”