The Circulating Glycosaminoglycan Signature of Respiratory Failure in Critically Ill Adults

Eric P Schmidt,Guoyun Li,Lingyun Li,Li Fu,Yimu Yang,Katherine H Overdier,Ivor S Douglas,Robert J Linhardt

doi:10.1074/jbc.m113.539452

Abstract

Systemic inflammatory illnesses (such as sepsis) are marked by degradation of the endothelial glycocalyx, a layer of glycosaminoglycans (including heparan sulfate, chondroitin sulfate, and hyaluronic acid) lining the vascular lumen. We hypothesized that different pathophysiologic insults would produce characteristic patterns of released glycocalyx fragments. We collected plasma from healthy donors as well as from subjects with respiratory failure due to altered mental status (intoxication, ischemic brain injury), indirect lung injury (non-pulmonary sepsis, pancreatitis), or direct lung injury (aspiration, pneumonia). Mass spectrometry was employed to determine the quantity and sulfation patterns of circulating glycosaminoglycans. We found that circulating heparan sulfate fragments were significantly (23-fold) elevated in patients with indirect lung injury, while circulating hyaluronic acid concentrations were elevated (32-fold) in patients with direct lung injury. N-Sulfation and tri-sulfation of heparan disaccharides were significantly increased in patients with indirect lung injury. Chondroitin disaccharide sulfation was suppressed in all groups with respiratory failure. Plasma heparan sulfate concentrations directly correlated with intensive care unit length of stay. Serial plasma measurements performed in select patients revealed that circulating highly sulfated heparan fragments persisted for greater than 3 days after the onset of respiratory failure. Our findings demonstrate that circulating glycosaminoglycans are elevated in patterns characteristic of the etiology of respiratory failure and may serve as diagnostic and/or prognostic biomarkers of critical illness.

Highlights

Endothelial glycocalyx degradation contributes to the pathogenesis of critical illness
Circulating HS was correlated with intensive care unit (ICU) length of stay, a measure of patient outcome. These findings suggest that circulating glycosaminoglycan fragments may serve as both diagnostic and prognostic biomarkers in critical illnesses such as acute respiratory failure
LC-MS analyses revealed that circulating glycosaminoglycan concentrations varied according to the etiology of respiratory failure

Summary

Background

Endothelial glycocalyx degradation contributes to the pathogenesis of critical illness. Human studies of glycocalyx/ESL degradation during critical illness have primarily relied upon either intravital microscopy of vascular beds of uncertain clinical relevance (e.g. the sublingual microcirculation [8, 9]) or the detection of circulating glycocalyx fragments by immunoassay (6, 9 –13). We collected plasma from healthy donors as well as three groups of patients with respiratory failure: those mechanically ventilated for altered mental status (e.g. ischemic brain injury, intoxication), those with indirect injury to the lung (e.g. nonpulmonary sepsis, pancreatitis), and those with direct lung injury (e.g. pneumonia, aspiration). Circulating HS was correlated with ICU length of stay, a measure of patient outcome These findings suggest that circulating glycosaminoglycan fragments may serve as both diagnostic and prognostic biomarkers in critical illnesses such as acute respiratory failure

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION