Urinary cysteinyl leukotrienes as biomarkers of endothelial activation, inflammation and oxidative stress and their relationship with organ dysfunction in human septic shock

Abstract

Background: Vascular leakage due to endothelial damage is a hallmark of sepsis and an important contributor to multi-organ failure. The proinflammatory mediators cysteinyl leukotrienes (CysLT) exert deleterious effects in the vasculature, being among the most potent vascular leakage promoting agents. However, their role in human sepsis or septic shock (SS) has been scarcely explored. We aimed at evaluating CysLT at admission and during hospitalization, as well as their correlation with endothelial dysfunction, inflammation, oxidative stress and renin-angiotensin-aldosterone system markers in SS patients. Furthermore, CysLT relationship with cardiac, renal, respiratory and hepatic parameters was also assessed. Methods: Patients with SS (n=20) and controls (blood donors, n=20) were included. Blood and spot urine samples were collected at days 1-2, days 3-4 and days 5-8 in SS patients and at a single time point in controls. Urinary CysLT (U-CysLT) and isoprostanes, plasma and urinary angiotensinogen (AGT), serum myeloperoxidase and IL-10 were quantified by ELISA. Serum intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, tumour necrosis factor-α, IL-1β and IL-6 were measured by multiplex immunoassays. Routine cardiac, renal and hepatic markers were evaluated using automated analyzers. Respiratory parameters were measured by arterial blood gas analysis. Results: At admission (days 1-2), SS patients had significantly higher U-CysLT values (p<0.01), exacerbated endothelial activation, inflammation and oxidative stress, augmented plasma and urinary AGT, cardiac and hepatic injury and respiratory and renal dysfunction. There were no significant changes in U-CysLT values during hospitalization. U-CysLT positively correlated with endothelial activation, inflammation, oxidative stress, plasma and urinary AGT and also with renal and hepatic injury markers. Conclusions: U-CysLT are associated with the pathophysiological processes underlying SS and appear to be potential non-invasive biomarkers for the clinical management of SS patients, as well as putative therapeutic targets.