Sepsis: Redox Mechanisms and Therapeutic Opportunities

Abstract

DESPITE ADVANCEMENTS IN THE treatment of critically ill patients, sepsis remains the leading cause of death in the ICU-an estimated 175,000 deaths per year (2). The incidence of sepsis in the United States ranges from 400,000 to 750,000 cases per year. Mortality due to sepsis is around 30% and increases with age from 10% in children to 40% in the elderly; mortality is 50% or greater in patients with the more severe syndrome, septic shock, and a recent study reported a 70% increase in the number of severe sepsis cases from 1993 to 2003 (2,5).Sepsis is a complex syndrome characterized by hyperinflammation, oxidative damage, hypercoagulation, tissue hypoperfusion and hypoxia, immune suppression, as well as multiorgan dysfunction. The pathogenesis of sepsis involves cumulative dysfunction of immune cells (macrophages, neutrophils, and lymphocytes), endothelial cells, and epithelial cells. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) significantly contribute to the dysfunction of these cells during sepsis.ROS/RNS play a key role in physiologic cellular functions, including signal transduction involved in expression of several cytokines, growth factors, and hormones. Additionally, ROS produced by the NADPH oxidase complex during phagocytosis is essential for microbicidal activity. However, excess production of ROS/RNS represents a key element in the cascade of deleterious processes in sepsis. Recent studies indicated that ROS can affect the pathogenesis of sepsis by two mechanisms: (a) modulating the innate immune signaling cascade, and (b) causing pathologic damage to cells and organs (1,4,6,11,13,16). ROS can alter LPS-TLR4 signaling at multiple levels and prime the innate immune cell for increased responsiveness to subsequent stimuli (14,17). ROS, such as superoxide and hydrogen peroxide, enhance NF-κB activation (3). More recently, ROS were shown to mediate trafficking of the TLR4 receptor to lipid rafts (16,17). Oxidative stress generated during hemorrhagic shock caused increase translocation of TLR4 receptor to the lipid rafts in the plasma membrane of macrophages that increased responsiveness to subsequent stimuli (17). Choi's group (16) also showed that carbon monoxide generated from heme oxygenase inhibits LPS-induced translocation of TLR4 to lipid rafts, as well as its downstream signaling adapter molecules (MYD88, TRIF, TRAF6, IRAK) through suppression of NADPH oxidase-dependent ROS generation (16).Superoxide anion and peroxynitrite play key roles in the pathogenesis of hemodynamic instability and organ dysfunction during septic shock. A growing body of evidence relates neutrophil dysfunction with the severity of sepsis and is linked with end-organ failure and mortality (8). Excessive release of proinflammatory mediators, ROS, and proteases by activated neutrophils exacerbates sepsis by increasing inflammation, oxidative tissue damage, Address reprint requests to:

Effect of induced mild hypothermia on two pro-inflammatory cytokines and oxidative parameters during experimental acute sepsis

“…During sepsis, many studies have shown that ROS and RNS may play a central pathogenic role. 8,9 Among ROS, HO…”

“…6 These reactive species represent a key element in the deleterious cascade process when endogenous antioxidant defences (for example, superoxide dismutase: SOD and catalase: CAT) 7 are overcome and/or when a redox imbalance occurs. 8,9 In sepsis several potential ROS sources, including mitochondrial electron transport and NADPH oxydase through macrophages and neutrophils activity, 7 are thought to be responsible for such an event leading to severe dysfunction and/or damage across multiple organs. 10 For example, NO generated within macrophages and other immune system cells, is implicated in pathologic vasodilatation resulting in hypotension.…”

Acute reactive oxygen species (ROS)-dependent effects of IL-1β, TNF-α, and IL-6 on the glomerular filtration barrier (GFB) in vivo

“…Small increases in one or the other can change intracellular signaling, causing changes in cellular actions. ROS and oxidative damage are known to been involved in the development of sepsis, and ROS are involved in the expression of cytokines as well (12). Clinical studies on treatment with antioxidants have by some authors been reported as promising (56), but due to conflicting results the clinical use of antioxidants has not yet been recommended by international sepsis guidelines (20).…”

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

“…Several studies have shown that ROS modulates TLR signaling (25,26). Because Nrf2 regulates several antioxidant defenses (see Table E1), we investigated inflammatory response in peritoneal macrophages isolated from LysM-Keap1 2/2 , LysMNrf2 2/2 , Keap1 f/f , and Nrf2 f/f toward different TLR ligands (TLR4-LPS, TLR3-Poly[I:C], TLR9-CpG, TLR2-LTA) and H 2 O 2 .…”