Background
Sepsis-related acute lung injury (ALI), characterized by increased lung permeability and inflammation, remains a significant cause of mortality in critically ill patients. Understanding the immunopathology of sepsis may point to novel treatment strategies. Recent studies show that products of hemolysis (plasma-free hemoglobin and heme) are increased in sepsis. Additionally, our studies have shown elevated levels of proline-glycine-proline (PGP) peptides derived from extracellular matrix proteins, which promote lung leak through CXCR2 activation. This study investigates the interrelationship between PGP and hemolysis in human sepsis.

Methods
We performed a prospective observational cohort study in which patients admitted to the University of Alabama at Birmingham Hospital with sepsis were enrolled within 24 hours of diagnosis. Patients at The Lung Health Center and non-sepsis ICU patients served as controls. Blood was collected, and plasma was separated by centrifugation. Plasma-free hemoglobin and heme were measured by spectral deconvolution. Haptoglobin and hemopexin were measured in plasma using ELISA. PGP was measured by Mass Spectrometry.

Results
Thirty-five healthy controls, thirty-eight ICU controls, twenty severe sepsis subjects, and forty-seven septic shock subjects were enrolled. More than 50% of the subjects were female, with a median age of 58 years. The total plasma PGP count increased with illness severity. Plasma haptoglobin levels increased with illness severity, while plasma hemopexin levels decreased. No significant relationship between PGP and plasma haptoglobin levels was observed, suggesting that haptoglobin is less likely a regulator of PGP-mediated acute lung injury. Interestingly, we observed an inverse relationship between plasma hemopexin levels and PGP levels. As plasma hemopexin levels rose, PGP declined. Together, these data suggest that free heme, which is regulated and scavenged by hemopexin, may influence PGP formation.

Conclusions
This study reveals a significant association between illness severity in sepsis and plasma levels of PGP, haptoglobin, and hemopexin. Our data suggest the potential for PGP peptides as biomarkers for sepsis-related injury and reveal a novel potential link between plasma-free heme and PGP. Ongoing studies are testing mechanisms by which heme and PGP are interrelated and how these mediators may mediate end-organ injury in sepsis.

References and Resources

N/A