Cell-free hemoglobin upregulates pulmonary endothelial heparanase expression to drive glycocalyx destruction and inflammation in sepsis.

Summary

Using human sepsis samples, a murine peritonitis model, endothelial heparanase deletion, and human pulmonary endothelial cells, the study identified a CFH–heparanase pathway driving endothelial glycocalyx degradation and inflammation. Oxidized CFH increased heparanase expression and activation, whereas endothelial heparanase deletion or acetaminophen attenuation reduced glycocalyx injury and inflammatory effects.

Key Findings

• In human sepsis, higher circulating cell-free hemoglobin was associated with increased heparanase and heparan sulfate levels and adverse clinical outcomes.
• Cell-free hemoglobin increased pulmonary endothelial heparanase expression, glycocalyx degradation, and systemic and pulmonary inflammation in cellular and murine models.
• Endothelial heparanase deletion abrogated the deleterious effects of cell-free hemoglobin, while acetaminophen attenuated them.

Clinical Implications

The findings support investigation of therapies that reduce oxidized cell-free hemoglobin or inhibit endothelial heparanase to prevent microvascular dysfunction and organ injury. Clinical translation will require validation of circulating CFH and heparanase as treatment-selection or pharmacodynamic biomarkers.

Limitations

• The clinical component is primarily associative and does not establish whether the CFH–heparanase pathway is a modifiable determinant of patient outcomes.
• The therapeutic attenuation data with acetaminophen require validation in clinically relevant dosing and treatment-after-sepsis-onset models.

Future Directions

Future work should evaluate CFH oxidation state and heparanase activity as longitudinal biomarkers, test selective heparanase or hemoglobin-targeted interventions after sepsis onset, and determine whether specific sepsis phenotypes benefit from glycocalyx-directed therapy.