Distinct patterns of endothelial response to endotoxin in aged mice as compared to young mice.

Aging exacerbates organ injury in endotoxemia, but it is not clear whether endotoxemia is associated with a specific, age-related profile of the endothelial response. Therefore, the aim of the study was to assess the pattern of endothelial response to lipopolysaccharide (LPS) in aged mice (18-month-old) as compared to young mice (3-month-old). Our analysis was based on functional endothelial responses measured in vivo by magnetic resonance imaging (MRI) and on a comprehensive panel of biomarkers of endothelial dysfunction measured by micro-flow liquid chromatography tandem mass spectrometry (microLC-MS/MS). In aged mice, the systemic inflammatory response (serum amyloid A, IL-1β, IL-2, eotaxin), kidney injury (urea), liver injury (ALT), and endothelial dysfunction induced by a relatively low dose of LPS (3 mg/kg) were all more pronounced as compared with young mice. Interestingly, in aged mice, LPS induced a different pattern of endothelial response compared to young mice, as evidenced by glycocalyx injury biomarkers (SDC-1, ESM-1), the endothelial permeability biomarkers (Angpt-2, sTie-2) and various hemostasis-related factors (sTM, TAFI, THBS-1). In contrast, biomarkers of endothelial inflammation (sVCAM-1, sICAM-1, sE-selectin, sP-selectin) and classical hemostasis biomarkers (PAI-1, t-PA, von Willebrand factor) displayed comparable responses to LPS in aged and young mice. In conclusion, aging does not indiscriminately potentiate LPS-induced inflammatory mediator generation in the current model of endotoxemia induced by a relatively low dose of LPS, but selectively alters the endothelial response in terms of glycocalyx injury, endothelial permeability, and hemostasis.