Preventive Leptin Administration Protects Against Sepsis Through Improving Hypotension, Tachycardia, Oxidative Stress Burst, Multiple Organ Dysfunction, and Increasing Survival.

Alejandro Vallejos,Pedro Olivares,Felipe Simon,Claudio Pérez-Leighton,Cesar Echeverria,Claudio Cabello-Verrugio,Diego Varela

doi:10.3389/fphys.2018.01800

Abstract

Sepsis syndrome is the most important cause of mortality in critically ill patients admitted to intensive care units (ICUs). However, current therapies for its prevention and treatment are still unsatisfactory, and the mortality rate is still high. Non-septic ICU patients are vulnerable to acquire sepsis syndrome. Thus, a preventive treatment for this population is needed. During sepsis syndrome and endotoxemia, severe hypotension, tachycardia, oxidative and immune response increase, multiple organ dysfunction syndrome (MODS) and decreased survival are observed. Leptin administration protects against negative effects of sepsis syndrome and endotoxemia. Furthermore, it is has been reported that leptin elevates blood pressure mediated by sympathetic nervous system activation. However, whether leptin administration before sepsis induction mediates its protective effects during sepsis through blood pressure regulation is not known. Therefore, we investigated whether pre-treatment of leptin improves blood pressure and MODS, resulting in survival increase during endotoxemia. The results showed that leptin administration before endotoxemia induction reduced both the hypotension and tachycardia characteristically observed during endotoxemia. Notably, this protective effect was observed early and late in the course of endotoxemia. Endotoxemia-induced MODS decreased in leptin-treated rats, which was reflected in normal values for liver and kidney function, inhibition of muscle mass wasting and maintenance of glycemia. Furthermore, leptin pre-treatment decreased the oxidative stress burst in blood and blunted the increased pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 observed during endotoxemia. Remarkably, according to the leptin-induced increase in survival, leptin pre-administration decreased the risk for death associated with sepsis syndrome at early and late times after endotoxemia induction. These results show a potential preventive therapy against sepsis syndrome and endotoxemia in vulnerable patients, based in the beneficial actions of leptin.

Highlights

Sepsis is the most important cause of mortality in critically ill patients admitted to intensive care units (ICUs) (Riedemann et al, 2003; Zarbock et al, 2014)
Leptin treatment decreased the oxidative stress burst in the blood and blunted the increased pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6 observed during endotoxemia
Despite some results that have suggested the beneficial effects of leptin administration toward increasing survival during endotoxemia and sepsis syndrome, the role of leptin as a potential preventive therapy against sepsis syndrome and endotoxemia is far from being demonstrated

Summary

Introduction

Sepsis is the most important cause of mortality in critically ill patients admitted to intensive care units (ICUs) (Riedemann et al, 2003; Zarbock et al, 2014). Sepsis syndrome is frequently supported by endotoxemia, which is the accumulation of large amounts of Gram-negative bacterial endotoxin, such as lipopolysaccharide (LPS), in the bloodstream (Karima et al, 1999; Riedemann et al, 2003; Pinsky, 2004). A number of basic and clinical studies have addressed sepsis syndrome and endotoxemia; current therapies used to treat it and its sequelae are unsatisfactory, and the mortality rate remains high (Rivers and Ahrens, 2008; Winters et al, 2010). The non-septic ICU population and the severely sick patients, are especially susceptible to the sepsis syndrome. Preventive therapies are fundamentally significant for those patient populations

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