Role of Free Radicals in Sepsis: Antioxidant Therapy (original) (raw)
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Fighting the stranger—antioxidant protection against endotoxin toxicity
Toxicology, 2002
Septic shock is a serious problem in critically ill and surgical patients throughout the world. It is a systemic inflammatory response caused by excessive secretion of proinflammatory mediators, such as tumor necrosis factor-a, mainly induced by endotoxin, a major component of the Gram-negative bacterial outer membrane. Experimental evidence suggests that reactive oxygen species (ROS) may be important mediators of cellular injury during endotoxemia, either as a result of macromolecular damage or by interfering with extracellular and intracellular regulatory processes. In addition, nitric oxide is thought to play a key role in the pathogenesis of sepsis. This review begins with a brief overview of the toxic effects of endotoxin at organism level, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, which then respond to bacterial infection and the pathway leading to nuclear factor-kB activation and proinflammatory gene transcription. With regard to this process, the review focuses on the involvement of reactive oxygen and nitrogen species. Lastly, the protective role of antioxidants against endotoxin toxicity and their potential clinical use is discussed.
Reactive Oxygen Species ( Ros ) Generation in Sepsis
2013
Sepsis and septic shock remain as leading cause of death in adult intensive care units. It is widely accepted that sepsis and septic shock are caused predominantly by gram-negative bacteria and their endotoxins. Endotoxin or Lipopolysaccharide (LPS) have important roles as host responses and trigger the inflammatory processes, caused by gram-negative bacterial infection. Production of oxygen radicals by neutrophils and macrophages such as reactive oxygen species (ROS), NO (nitric oxide) and peroxynitrite promote gene expression of proinflammatory mediators. Enhanced generation of ROS well be responsible for tissue injury in septic shock and endotoxemia. Oxidative stress is defined as an unbalance between oxidants and antioxidants. Antioxidant capacity may be compromised in patients with severe infections and high levels of the metabolic products of free radical damage can be observed. The aim of this review is to inspect the play role of inflammatory mediators with oxidative stress ...
Antioxidants
Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-i...
Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment?
Redox report : communications in free radical research, 2015
Sepsis is a clinical syndrome characterized by systemic inflammation, usually in response to infection. The signs and symptoms are very similar to Systemic Inflammatory Response Syndrome (SIRS), which typically occur consequent to trauma and auto-immune diseases. Common treatments of sepsis include administration of antibiotics and oxygen. Oxygen is administered due to ischemia in tissues, which results in the production of free radicals. Poor utilization of oxygen by the mitochondrial electron transport chain can increase oxidative stress during ischemia and exacerbate the severity and outcome in septic patients. This course of treatment virtually mimics the conditions seen in ischemia-reperfusion disorders. Therefore, this review proposes that the mechanism of free radical production seen in sepsis and SIRS is identical to the oxidative stress seen in ischemia-reperfusion injury. Specifically, this is due to a biochemical mechanism within the mitochondria where the oxidation of su...
The Journal of Infection in Developing Countries, 2016
Introduction: Sepsis is a complex inflammatory syndrome with diverse etiology and wide spectrum of severity. The aim of this study was to investigate whether inflammatory mediators, in comparison with oxidative parameters, are associated with severity of sepsis. Methodology: Plasma neopterin, adenosine deaminase (ADA), vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-α), as inflammatory mediators, and serum nitric oxide (NOx), nitrotyrosine (NT), oxidized LDL (oxLDL) levels, serum paraoxonase 1 (PON1) activity, and erythrocyte glutathione (GSH) levels as oxidative stress parameters of 12 patients with mild sepsis, 25 patients with severe sepsis, and 20 healthy control subjects were evaluated. NOx, GSH levels and PON1 activity were determined by colorimetric methods, whereas neopterin, VCAM, ICAM, IL-1, IL-6, TNF-α, NT, and oxLDL levels were measured by enzyme-linked immunosorbent assay (ELI...
Vaccines
Oxidative stress resulting from the disproportion of oxidants and antioxidants contributes to both physiological and pathological conditions in sepsis. To combat this, the antioxidant defense system comes into the picture, which contributes to limiting the amount of reactive oxygen species (ROS) leading to the reduction of oxidative stress. However, a strong relationship has been found between scavengers of ROS and antioxidants in preclinical in vitro and in vivo models. ROS is widely believed to cause human pathology most specifically in sepsis, where a small increase in ROS levels activates signaling pathways to initiate biological processes. An inclusive understanding of the effects of ROS scavenging in cellular antioxidant signaling is essentially lacking in sepsis. This review compiles the mechanisms of ROS scavenging as well as oxidative damage in sepsis, as well as antioxidants as a potent therapeutic. Direct interaction between ROS and cellular pathways greatly affects sepsi...
Countervailing Influence of Tumor Necrosis Factor-α and Nitric Oxide in Endotoxemia
Journal of the American Society of Nephrology, 2001
Tumor necrosis factor-␣ (TNF-␣), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-␣ exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-␣ and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 Ϫ/Ϫ), TNF-R2 (R2 Ϫ/Ϫ), or both receptors (R1R2 Ϫ/Ϫ) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-␣ production but failed to induce glomerular thrombosis. Concomitant administration of LPS ϩ NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperito-
Countervailing influence of tumor necrosis factor-alpha and nitric oxide in endotoxemia
Journal of the American Society of Nephrology : JASN, 2001
Tumor necrosis factor-alpha (TNF-alpha), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-alpha exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-alpha and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 -/-), TNF-R2 (R2 -/-), or both receptors (R1R2 -/-) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-alpha production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-alpha synthesis and prevented glomerular...