Interaction between Systemic Endothelial Glycocalyx Fragility and Brain Dysfunction in Aged Sepsis Survivors

About This Grant

Project Summary/Abstract Sepsis, the body’s injurious response to infection, afflicts nearly 50 million people worldwide annually with a particularly high burden in older patients. The majority of sepsis survivors experience prolonged or permanent brain dysfunction. We have recently discovered that this form of post-septic impairment is partially driven by a pathologic organ crosstalk between the systemic vasculature and brain, a process that may be exacerbated by age. The endothelial glycocalyx, a heparan sulfate (HS)-rich layer that lines the lumen of all blood vessels, is degraded during sepsis, releasing highly biologically active HS fragments into circulation. These circulating HS fragments selectively deposit within the hippocampus and can worsen cognitive outcomes in sepsis survivors. Strikingly, circulating HS levels are 5-fold higher in older (≥65) compared to younger patients (<50) with sepsis. This aging-associated increase in HS shedding may be due to a more fragile endothelial glycocalyx. In preliminary preclinical studies, we have found that increased age was associated with ultrastructural changes of the glycocalyx, including a loss of 6-O sulfation residues within endothelial-derived HS. Loss of 6-O sulfation is known to increase HS susceptibility to degradation by heparanase, the “sheddase” responsible for glycocalyx degradation during sepsis. This loss of sulfation may be due to increased circulating Sulfatase-2 (Sulf2) an enzyme dedicated to removal of 6-O sulfates from HS as 1) preliminary single cell RNA sequencing of peripheral blood mononuclear cells demonstrated that aged humans have increased levels of Sulf2 in monocytes and 2) aged mice exhibited increased blood Sulf2 activity. Based on these preliminary observations, we hypothesize that age-related remodeling of endothelial HS by monocyte-derived Sulf2 predisposes older patients to release brain-penetrating HS during sepsis, which will be associated with post-septic brain dysfunction. We will rigorously test this hypothesis in both pre-clinical models of sepsis and a prospective, observational cohort of patients with sepsis. We will specifically 1) determine whether age-related increases in expression of Sulf2 in monocytes are responsible for endothelial glycocalyx fragility in older mice; 2) determine whether age-related increases in expression of Sulf2 in monocytes exacerbate pathogenic HS deposition during sepsis in aged mice; and 3) identify whether circulating pathogenic HS fragments are associated with impairment in multiple cognitive domains in older sepsis survivors. This work will mechanistically investigate a unique form of age-related pathologic interorgan communication: release of brain-penetrating, pathogenic HS from the systemic vasculature. Critically, it may also identify Sulf2 inhibition as a therapeutic target in sepsis, which could improve the lives of millions of older survivors per year.