Novel relationships between oxidative stress and angiogenesis-related factors in sepsis: New biomarkers and therapies

Figures & data

Figure 1. Pathophysiology of sepsis. Several elements are crucial in the progression of the disease, such as the release of large quantities of pro-inflammatory mediators, complement activation, and dysregulated coagulation. Moreover, some individuals may be genetically susceptible to developing sepsis. The excess inflammation from sepsis may be followed by immunosuppression, leading to organ dysfunction. Oxidative stress also contributes to organ dysfunction, leading to more severe forms of the disease. The segmented arrow involves inhibition of NF-κB by anti-inflammatory cytokines. DIC = disseminated intravascular coagulation; MODS = multisystem organ dysfunction syndrome; NF-κB = nuclear factor κB; NO = nitric oxide; PAMPs = pathogen-associated molecular patterns; PMNs = polymorphonuclear leukocytes; RNS = reactive nitrogen species; ROS = reactive oxygen species; SIRS = systemic inflammatory response syndrome.

Figure 2. Proposed integration between oxidative stress and angiogenesis-related factors (ARF). (i) In infection, PAMPs of bacteria activate TLRs, in cells such as macrophages. (ii) Oxidative stress generated in sepsis activates TLRs through CEP adducts. (iii) VEGF levels increase at onset of severe sepsis, being stimulated by ROS/RNS and by HIF-1α, but as severe sepsis progresses, VEGF levels decrease. (iv) DIC, present in severe sepsis, is one of the main conditions that results in an increase in the Ang-2/Ang-1 ratio and decreases VEGF levels. Both levels of these ARF are related to endothelial dysfunction through microcirculatory dysfunction. (v) Mitochondrial dysfunction leads to septic shock, mainly through myocardial dysfunction. The dotted arrow implicates the inhibition of HIF-1α by a rise in cellular O₂ concentration due to mitochondrial dysfunction (cytopathic hypoxia). Ang-2 = angiopoietin-2; DIC = disseminated intravascular coagulation; HIF-1α = hypoxia-inducible factor 1α; MODS = multisystem organ dysfunction syndrome; NF-κB = nuclear factor κB; ROS = reactive oxygen species; RNS = reactive nitrogen species; TLR = toll-like receptor; VEGF = vascular endothelial growth factor.

Table I. Biomarkers of sepsis. Different types of biomarkers have been proposed. Despite no single biomarker of sepsis being ideal, many of them are helpful identifying critically ill patients.

	Biomarkers	References
Inflammatory biomarkers	CRP, IL-1β, IL-1ra, IL-6, IL-8, IL-18, MCP-1, MIF, NK cells, PCT, MR-ProADM, TNFα	83, 87, 88, 89, 92, 93, 95, 107
Complement proteins	C5a	89, 93
Activated neutrophils and monocytes	CD14, CD64, HBP, HMBG1, LBP, sRAGE, TREM-1	87, 88, 89, 92, 93
Immunosuppression	IL-10	89
Organ dysfunction	Lactate, NGAL, pro-ANP, hFABP	88, 89, 92, 93
Hemostasis	D-dimer	72, 96
Endothelial dysfunction	von Willebrand factor, ADAMTS 13	72, 110, 115
	Endocan	72, 115
	Selectins, VCAM-1, ICAM-1	72, 88, 107, 110, 115
	ET-1	72, 115
	uPA	72, 93
Oxidative damage	MDA	97, 98
	F2-isoprostanes	29, 97, 99
	TBARS, xantine oxidase, MPO	8, 100
Antioxidant potential	SOD, CAT, GPx	18, 95
	SH group donors, Vitamins E, C, β-carotene	8, 18, 91
Angiogenesis-related biomarkers	VEGF	58, 60, 66, 72, 77, 110, 115
	sFlt-1	53, 57, 72, 105, 107, 110, 115
	Ang-1 and -2	56, 72, 93, 110, 111, 112, 115
	PDGF, PlGF, FGF, PAI-1	55, 56, 72, 107, 109, 114

ADAMTS 13 = a disintegrin and metalloproteinase with thrombospondin motifs 13; Ang = angiopoietin; pro-ANP = precursor of atrial natriuretic peptide; C5a = complement protein 5 activated; CAT = catalase; CD = cluster of differentiation; CRP = C-reactive protein; ET-1 = endothelin-1; FGF = fibroblast growth factor; sFlt-1 = soluble Fms-like tyrosine kinase-1; GPx = glutathione peroxidase; HBP = heparin-binding protein; hFABP = heart-type fatty acid-binding protein; HMBG1 = high-mobility group box 1; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; LBP = lipopolysaccharide-binding protein; MCP = monocyte chemoattractant protein; MDA = malondialdehyde; MIF = macrophage migration inhibitory factor; MPO = myeloperoxidase; NGAL = neutrophil gelatinase-associated lipocalin; NK = natural killer; PAI-1 = plasminogen activator inhibitor-1; PCT = procalcitonin; PDGF = platelet-derived growth factor; ProADM = proadrenomedullin; sRAGE = soluble receptor for advanced glycation end-products; SH = sulfhydryl; SOD = superoxide dismutase; TBARS = thiobarbituric acid reactant substances; TNFα = tumor necrosis factor α; TREM-1 = triggering receptor expressed on myeloid cells 1; uPA = urokinase plasminogen activator; VCAM-1 = vascular cell adhesion molecule-1; VEGF = vascular endothelial growth factor.

Table II. Novel therapeutic options for sepsis.

	Therapeutic agents	Mechanism of action	Study setting	Observed outcome	Ref.
Antioxidant molecules	Vitamin A	NF-κB inhibition	LPS-mice models of sepsis	Decreased NF-κB activity	133
	Vitamin E	Reduce O2^•− levels in septic patients through NOx inactivation	Ex-vivo human samples	Decreased O2^•− plasma levels	134
	Vitamin C	Electron donor (reducing agent). Inhibition of NOx and inducible nitric oxide synthase	CLP induced sepsis mice models	Increased survival	20, 135
	Selenium	Increase activity of GSH-Pxs and thioredoxin reductases families	Multi-center study in patients with SIRS, sepsis, and septic shock	Reduced mortality	20, 136
Mitochondrial-targeted antioxidants	Mito Q	Active ubiquinol in the respiratory chain	LPS sepsis model	Decreased organ dysfunction	137
	Mito VitE	Vitamin E accumulation on the mitochondria	Non-septic mice	Increased plasma SOD activity and urinary isoprostane concentration	138, 139
	Hemigramicidin-TEMPOL	Catalyzes the removal of superoxide anion, limits hydroxyl radical formation from hydrogen peroxide, and accepts an electron to form the antioxidant hydroxylamine	Non-preclinical or clinical studies		140
Endothelial dysfunction correction	BH4	Prevents eNOS uncoupling	Sheep model of sepsis	Attenuation of microvascular impairment and prolonged survival	129
Angiogenesis-related molecules	Bevacizumab	Anti-VEGF antibody, prevents endothelial barrier disruption	Mice model of sepsis	Increased survival	131
	Vasculotide	Ang-2 antagonist, increases Tie-2 receptor activity	CLP mice septic model	Reduced mortality	132

Ang-2 = angiopoietin 2; BH4 = tetrahydrobiopterin; CLP = cecal ligation and puncture; eNOS = endogenous nitric oxide synthase; GSH-Pxs = glutathione peroxidases; NF-κB = nuclear factor κB; O₂^•2 = superoxide anion radical; Tie-2 = tyrosine kinase with immunoglobulin-like and EGF-like domains 2; VEGF = vascular endothelial growth factor.

Table III. Remaining questions and focus of future research.

Remaining for future research	Possible approaches
It remains to be answered why there are so many innovative interventions for sepsis based in antioxidant strategies which have been effective in preclinical stages but have failed in controlled trials	Probably the answer lies in that current preclinical sepsis models do not adequately represent the clinical settings, mainly due to differences in the onset of treatment. Therefore molecules with effectiveness in models of advanced sepsis should be selected for clinical trials
It is also necessary to establish the effect of oxidative stress on angiogenesis-related factors and vice versa in order to validate the proposed model of integration	This review proposes many connections between both pathological aspects of sepsis. A method to answer this question is through preclinical studies in which the effect of antioxidant therapies in angiogenic parameters are evaluated, and vice versa; e.g. how VEGF levels on mitochondrial antioxidant treatment groups differ from non-treatment mice.
It remains also important to determine if it is possible to develop a panel of multiple markers which can be used as an ideal biomarker	An observational cohort study should be performed to answer this question, measuring antioxidant and angiogenic biomarkers and correlating them to clinical features through a multivariable analysis. The model by Wong et al. (116) is proposed as a well-designed study.

Wong HR, Lindsell CJ, Pettilä V, Meyer NJ, Thair SA, Karlsson S, et al. A multibiomarker-based outcome risk stratification model for adult septic shock. Crit Care Med. 2014;42:781–9.

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