Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention
Abstract
:1. Introduction
2. Disseminated Intravascular Coagulation in Sepsis
3. Vascular Haemostasis in Sepsis
3.1. Endothelium
3.2. Platelets
3.3. Neutrophils
4. Oxidative and Nitrosative Stress
5. The Role of Oxidative and Nitrosative Stress in Sepsis-Related Haemostasis
5.1. Glycocalyx
5.1.1. Mitochondria
5.1.2. NADPH Oxidase
5.1.3. iNOS and NO
5.2. Platelets
6. Conclusions
Funding
Conflicts of Interest
References
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Enzyme | Mechanism | Reference |
---|---|---|
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX1-5; DUOX1, 2) | Conversion of O2 to O2•−, NADPH acts as an electron donor. NOX1–4 provide constitutive activity, which is dependent on subunits NOXO1, p47phox, or p22 phox phosphorylation. Further rearrangement of the subunit complexes p40phox, p67phox, and Rac from the cytosol to the membrane allows for transfer of electrons from the substrate to O2. NOX5 and Duox activation are calcium-dependent. | [90,91,92] |
Mitochondrial respiration chain | Oxygen acts as the terminal electron acceptor of the respiratory chain. The process involves a four-electron reduction of oxygen to water, which can occur in the outer membrane, in the inner membrane, or within the matrix. ROS including O2•−, H2O2, and •OH are produced as intermediates in this ongoing process. Around 1% of O2•− exits the mitochondria as a physiological process under steady-state conditions. Hyperoxia and hypoxia/reperfusion both augment O2•− release greatly, with the potential for direct effects on cellular redox state and signaling, as well as the conversion to more damaging species through iron catalysis (Fenton reaction). | [93,94,95,96,97] |
Cyclooxygenase and Lipoxygenase | These enzymes metabolize arachidonic acid (AA) to form prostaglandins, thromboxane, and leukotrienes. The enzymic addition of oxygen as occurs in these processes involves ROS generation with the potential for collateral effects. In addition, COX and LOX metabolites are known to affect intracellular redox balance by activation of NOX enzymes. | [98,99] |
Xanthine, oxidoreductase (XO), dehydrogenase oxidase (XDH) | Rate-limiting enzymes responsible for the conversion of hypoxanthine and xanthine to uric acid in the last stages of purine catabolism. XDH catalyses these process, utilising NAD+ as a cofactor. XDH can be readily converted to XO by hyperoxia, by the effects of ischaemia/reperfusion, or by limited proteolysis. XO catalyses the same reaction, but uses oxygen as a co-factor rather than NAD+; consequently, O2•− and H2O2 are generated as by products and thus influence an array of ROS-related dysfunctions. | [71,100,101] |
Nitric oxide synthase (NOS) NOS1 or nNOS (neuronal), NOS2 or iNOS (inducible), and NOS3 or eNOS (endothelial) | Enzymatic production of NO and regulation of vascular tone. Use of l-arginine and O2 as substrates and nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R)5,6,7,8-tetrahydrobiopterin (BH4) as reduced cofactors. When NO is produced by endothelial cells, it diffuses through smooth muscle cells, binding to guanylyl cyclase (GC). GC produces the second messenger, cyclic guanosine 3,5-monophosphate (cGMP). cGMP interacts with protein kinase G (PKG), which promotes the phosphorylation of contractile proteins, resulting in a decrease in cytosolic Ca2+, which stimulates myosin light-chain dephosphorylation, promoting vasorelaxation. Formed by the reaction between equimolar amounts NO and O2•−, the peroxnitrite ion (ONOO−) is more reactive and toxic than NO. It modifies proteins and peptides via nitration (of tyrosine) and nitrosylation (of thiol moieties) and, in addition, via hydroxylation reactions involving a species likened to •OH. ONOO− formation and damage is strongly correlated with a range of cardiovascular pathologies. | [101] |
Therapy | Mechanism | Positive Effect | Why is Not it Been Clinically Used? |
---|---|---|---|
Vitamin C | Potent ROS scavenging antioxidant agent [138] | Septic shock patients treated with ANON®, an antioxidant-enriched concentrated liquid diet with high concentrations of vitamin C and E, demonstrated a restoration of vitamin C radical levels in serum and a reduction in MOF [139]. Septic animals treated with vitamin C showed an improvement in microvascular dysfunction and microvascular permeability barrier integrity, inhibition of iNOS expression, and ameliorated hypotension [89,113,138,140]. The vasodilatation and reduction in vitamin C plasma concentration after low doses of LPS administration in healthy volunteers were reversed by co-administration of vitamin C [141]. | Limited clinical trials |
Seleniun | A micronutrient fundamental for GPx synthesis [142,143] | The administration of high levels of sodium selenite intravenously showed an increase in blood selenium concentration and GPx activity and significantly decreased mortality of septic patients with DIC [144]. | Seleniun decreased the infection in nonseptic patients only. Clinical trials did not show any improvement in outcomes in a general septic patient population [145] |
N-acetylcysteine (NAC) | Antioxidant is able to restore the levels of GSH in the cells and also acts as an anti-inflammatory agent [146] | The treatment of rats with NAC, 30 min after LPS injection, re-established their ROS generation levels and platelet aggregation [124]. NAC treatment in rats decreased neutrophil infiltration and leukocyte adherence, ameliorated mitochondrial dysfunction, and decreased oxidative stress [147,148,149,150]. NAC administration by septic patients reduced lipid peroxidation, induced tissue oxygenation, ameliorated cardiac function, and decreased the mortality rate [151,152,153,154]. | Conflicting results: some studies showed that NAC did not improve outcome for patients or affect levels of cytokines’ release [155]. NAC can also worsen organ failure [156]. Findings need to be confirmed in larger clinical trials |
MitoQ | Targets mitochondrial dysfunction [157] | Endotoxemic rats that received MitoQ by i.v. administration demonstrated enhancement in mitochondria respiration, decreased levels of oxidative stress and IL-6, and improved organ dysfunction [157,158]. | There are no data from human studies |
Superoxide dismutase (SOD) | Converts superoxide radical into hydrogen peroxide and molecular oxygen (O2), while the catalase and peroxidases convert hydrogen peroxide into water [159,160] | The M40401 SOD mimetic restored vascular reactivity, regulated arterial pressure, and decreased mortality levels of rats infected with E. coli [161] | There are no data from human studies |
Nitric oxide scavenger | The compound pyridoxylated haemoglobin polyoxyethylene (PHP) is a chemically altered human-derived hemoglobin used as an NO scavenger and SOD mimetic [162]. | In a Pseudomona aeruginosa sepsis model in sheep, infusion of PHP for 48 h restored a low mean arterial pressure and improved the systemic vascular resistance [163,164]. In phase I/II clinical trials, PHP increased blood pressure and diminished catecholamine requirement [165]; in a phase III trial with 377 patients, PHP reduced the necessity of vasopressor use [166]. | Despite some positive results, after 28 days of therapy with PHP, there was no benefit and indeed mortality rates increased, with a SOFA score higher than 13 [166] |
Melatonin | Secreted during the night, melatonin is a hormone produced by the pineal gland. It possesses anti-inflammatory properties and demonstrates antioxidant functions, acting as both an ROS and RNS scavenger [167]. | In septic rats induced by CLP, administration of melatonin improved organ injury; an effect that was ascribed to the capacity of melatonin to enhance GSH levels and to inhibit neutrophil aggregation [168]. In a placebo-controlled study with 12 healthy volunteers, the group that received melatonin before LPS showed lower levels of inflammatory markers and oxidative stress compared with the saline control group [138,169]. | Lack of clinical trials |
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Lopes-Pires, M.E.; Frade-Guanaes, J.O.; Quinlan, G.J. Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention. Antioxidants 2022, 11, 88. https://doi.org/10.3390/antiox11010088
Lopes-Pires ME, Frade-Guanaes JO, Quinlan GJ. Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention. Antioxidants. 2022; 11(1):88. https://doi.org/10.3390/antiox11010088
Chicago/Turabian StyleLopes-Pires, Maria Elisa, Jéssica Oliveira Frade-Guanaes, and Gregory J. Quinlan. 2022. "Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention" Antioxidants 11, no. 1: 88. https://doi.org/10.3390/antiox11010088
APA StyleLopes-Pires, M. E., Frade-Guanaes, J. O., & Quinlan, G. J. (2022). Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention. Antioxidants, 11(1), 88. https://doi.org/10.3390/antiox11010088