Urinary Cysteinyl Leukotrienes as Biomarkers of Endothelial Activation, Inflammation and Oxidative Stress and Their Relationship with Organ Dysfunction in Human Septic Shock

Abstract

Cysteinyl leukotrienes (CysLT) are potent vascular leakage-promoting agents but have been scarcely explored in human septic shock (SS). We evaluated CysLT at admission and during hospitalization and their correlation with endothelial dysfunction, inflammation, oxidative stress, the renin–angiotensin–aldosterone system, and cardiac, renal, respiratory, and hepatic parameters in SS patients. Blood and spot-urine samples were collected at days 1–2 (admission), 3–4, and 5–8 in SS patients (n = 13) and at a single time point in controls (n = 22). Urinary CysLT (u-CysLT) and isoprostanes, plasma, and urinary angiotensinogen, serum myeloperoxidase, and IL-10 were quantified by ELISA. Serum intercellular-adhesion molecule-1, vascular cell-adhesion molecule-1, E-selectin, tumor necrosis factor-α, IL-1β, and IL-6 were measured by multiplex immunoassays. Routine markers were evaluated using automated analyzers. At admission, SS patients had increased u-CysLT, endothelial activation, inflammation, oxidative stress, and plasma and urinary angiotensinogen, as well as cardiac, respiratory, hepatic, and renal injury/dysfunction. There were no changes in u-CysLT during hospitalization. Both correlation and multivariate analyses showed positive relationships of u-CysLT with endothelial activation, inflammation, oxidative stress, proteinuria, and hepatic injury/dysfunction markers. These results suggest that u-CysLT may be potential non-invasive biomarkers for monitoring the pathophysiological mechanisms underlying SS, as well as putative therapeutic targets.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients

“…Noteworthy, in critical COVID-19 patient groups, U-CysLT were also associated with hepatic injury/dysfunction, being positively correlated with AST and ALP and inversely correlated with albumin. Importantly, we also recently evidenced a positive association between U-CysLT and hepatic injury in septic shock patients, thus reinforcing the contribution of these mediators to liver damage [ 13 ].…”

“…In our study, critical COVID-19 groups also exhibited significant positive correlations of U-CysLT values with several systemic inflammatory markers and parameters, namely with the proinflammatory cytokines IL-6 and TNF-α, with CRP and with total leukocytes, neutrophils, eosinophils and NMR ratio. Interestingly, this relationship of U-CysLT with the inflammatory status was far more pronounced in critical COVID-19 patients than in septic shock patients recently evaluated by our group [ 13 ]. This suggests that U-CysLT could be more implicated in COVID pathogenesis, as also denoted by their association with prognosis.…”

“…Indeed, they exert several actions relevant for respiratory pathology, being able to stimulate mucous secretion and bronchial hyperresponsiveness, increase microvasculature permeability and stimulate eosinophil infiltration [ 10 – 12 ]. In addition, our group recently showed that urinary CysLT were positively correlated with endothelial activation, inflammation, oxidative stress, and hepatic dysfunction markers in septic shock patients [ 13 ]. CysLT, namely leukotriene C 4 (LTC 4 ), leukotriene D 4 (LTD 4 ) and leukotriene E 4 (LTE 4 ), are arachidonic acid-derived eicosanoids synthesized by the 5-lipoxygenase (5-LOX)/LTC 4 synthase pathway in immunocompetent cells (e.g., mast cells, neutrophils, eosinophils, basophils and monocytes) [ 14 , 15 ].…”