Abstract
BackgroundSeveral low-molecular-weight phenolic acids are present in the blood of septic patients at high levels. The microbial origin of the most of phenolic acids in the human body was shown previously, but pathophysiological role of the phenolic acids is not clear. Sepsis is associated with the excessive production of reactive oxygen species (ROS) in both the circulation and the affected organs. In this work the influence of phenolic acids on ROS production in mitochondria and neutrophils was investigated.MethodsROS production in mitochondria and neutrophils was determined by MCLA- and luminol-dependent chemiluminescence. The rate of oxygen consumption by mitochondria was determined polarographically. The difference of electric potentials on the inner mitochondrial membrane was registered using a TPP+-selective electrode. The formation of phenolic metabolites in monocultures by the members of the main groups of the anaerobic human microflora and aerobic pathogenic bacteria was investigated by the method of gas chromatography–mass spectrometry.ResultsAll phenolic acids had impact on mitochondria and neutrophils, the main producers of ROS in tissues and circulation. Phenolic acids (benzoic and cinnamic acids) producing the pro-oxidant effect on mitochondria inhibited ROS formation in neutrophils. Their effect on mitochondria was abolished by dithiothreitol (DTT). Phenyllactate and p-hydroxyphenyllactate decreased ROS production in both mitochondria and neutrophils. Bifidobacteria and lactobacilli produced in vitro considerable amounts of phenyllactic and p-hydroxyphenyllactic acids, Clostridia s. produced great quantities of phenylpropionic and p-hydroxyphenylpropionic acids, p-hydroxyphenylacetic acid was produced by Pseudomonas aeruginosa and Acinetobacter baumanii; and benzoic acid, by Serratia marcescens.ConclusionsThe most potent activators of ROS production in mitochondria are phenolic acids whose effect is mediated via the interaction with thiol groups. Among these are benzoic and cinnamic acids. Some phenolic acids, in particular phenyllactate and p-hydroxyphenyllactate, which decrease ROS production in mitochondria and neutrophils, can play a role of natural antioxidants. The results indicate that low-molecular weight phenolic acids of microbial origin participate in the regulation of the ROS production in both the circulation and tissues, thereby affecting the level of oxidative stress in sepsis.
Highlights
Several low-molecular-weight phenolic acids are present in the blood of septic patients at high levels
The effect of phenolic acids on the menadione-activated reactive oxygen species (ROS) production in mitochondria was determined by measuring the chemiluminescence of MCLA (cypridina luciferin analog 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazine-3-one)
It was found that phenolic acids, which increased of the menadione-activated ROS production, inhibited mitochondrial respiration, whereas with phenyllactate, phydroxyphenylacetate, and р-hydroxyphenyllactate statistically differences were not observed (Figure 2)
Summary
Several low-molecular-weight phenolic acids are present in the blood of septic patients at high levels. Sepsis is associated with the excessive production of reactive oxygen species (ROS) in both the circulation and the affected organs. Two stages of SIRS are recognized: the initial proinflammatory stage, which involves the activation of neutrophils, tissue macrophages, an increase in the production of cytokines and reactive oxygen species (ROS), and the later stage, which is characterized by a decrease in the level of cytokines and neutrophils, the appearance of the signs of multiple organ failure and persistent tissue hypoxia [4]. The prevalent hypothesis regarding the mechanisms of sepsis and septic shock indicates that this syndrome is caused by an excessive defensive and inflammatory responses characterized by an increased generation of ROS, nitric oxide (NO), and inflammatory cytokines [4,5]. In pathological complications, such as acute lung injury and sepsis, excess ROS production by neutrophils may influence vicinal cells of endothelium or epithelium, contributing to the inflammatory tissue injury [7,8]
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