Role of Oxidative Stress and Mitochondrial Dysfunction in Sepsis and Potential Therapies

Abstract

Sepsis is one of the most important causes of death in intensive care units. Despite the fact that sepsis pathogenesis remains obscure, there is increasing evidence that oxidants and antioxidants play a key role. The imbalance of the abovementioned substances in favor of oxidants is called oxidative stress, and it contributes to sepsis process. The most important consequences are vascular permeability impairment, decreased cardiac performance, and mitochondrial malfunction leading to impaired respiration. Nitric oxide is perhaps the most important and well-studied oxidant. Selenium, vitamin C, and 3N-acetylcysteine among others are potential therapies for the restoration of redox balance in sepsis. Results from recent studies are promising, but there is a need for more human studies in a clinical setting for safety and efficiency evaluation.

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…In critical illness, tissue oxygen consumption and total energy expenditure are increased, with intracellular metabolism boosted by up to 200% compared to the healthy state (193). Cells that represent the innate immune system, like neutrophils, and macrophages, are mainly responsible for the oxidative burst that takes place early in critical illness (194) along with the generation of ROS and nitrogen oxygen species (RNS) that are important for host defenses. In neutrophils of critically ill patients, oxidative activity correlates positively with the degree of intranuclear NF-κB expression (195).…”

“…Oxidative stress is a predictor of mortality in septic shock patients (198). Glutathione is one of the most important redox buffers of the cells, as it can be found in all cell compartments and acts as a cofactor of several enzymes, helps in DNA repair, scavenges ROS (e.g., hydroxyl radicals, hydrogen peroxide, and lipid peroxides), and generates other antioxidants, such as ascorbic acid (see section Hypovitaminoses) and tocopherols (194). Vitamins D and C upregulate glutathione synthesis and prevent depletion (see section Hypovitaminoses) (199,200).…”

“…The inclusion or exclusion of fludrocortisone, as a cointervention with hydrocortisone, may partly explain the differences reported in outcomes of some RCTs (see explanation for Figure 7 below) (292,298). Other potential co-interventions directed at increasing glucocorticoid receptor expression, such as statins (299), melatonin (300), beta-blockers (301), calcium channel blockers (301), or directed at improving mitochondrial function (194,302,303) have not been investigated in association with glucocorticoid treatment in acute illness or alone in chronic critical illness.…”

Sevoflurane suppresses oxidation-induced stress and inflammatory responses, via promotion of Nrf2-induced antioxidant signaling

“…These clinical studies demonstrate that low levels of antioxidant have an adverse influence on prognosis in septic patients. Mitochondrial injury in sepsisinduced oxidative stress might be the central mechanism involved in the intense inflammatory response and cellular apoptosis (Galley 2011;Quoilin et al 2014;Mantzarlis et al 2017). The peroxidation of the mitochondrial lipid cardiolipin, which is present in the inner mitochondrial membrane and is important for energy metabolism, leads to dissociation of cytochrome c and causes reduced ATP production, and even more ROS production.…”

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

“…It has been associated with neutrophil activity previously in obesity (147) and may be associated with mitophagy of redundant mitochondria (148). Defective mitochondrial activity has also been previously documented in sepsis (149,150). CD24 is considered to be predominantly a B cell marker (151), but it is also found on granulocytes and is implicated in early neutrophil responses to infection in sepsis-induced acute respiratory distress syndrome (152), along with other entities identified in this study-olfactomedin 4 (OLFM4), lipocalin 2 (LCN2), and bactericidal/permeability-increasing protein (BPI).…”