Clinical Evidence of Peroxynitrite Formation in Chronic Renal Failure Patients with Septic Shock

Fukuyama, Naoto; Takebayashi, Yoshihiro; Hida, Miho; Ishida, Hideyuki; Ichimori, Kohji; Nakazawa, Hiroe

doi:10.1016/s0891-5849(96)00401-7

Cited by 175 publications

(96 citation statements)

References 14 publications

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“…Furthermore, both IVVM and immunohistochemistry revealed RNS generation in tubular vacuoles. The potential clinical relevance of these findings is supported by the detection of nitrated plasma proteins in patients with sepsis and renal failure (13).…”

Section: Discussionmentioning

confidence: 87%

“…It has also been proposed that reactive nitrogen species (RNS) derived from iNOS may contribute to the development of sepsis-induced AKI. This notion is supported by the appearance of nitrated plasma proteins in the patient with sepsis and kidney injury (13) and the appearance of nitrated proteins and oxidation products in the kidney during LPS-induced renal injury in rats (14,15). Although the generation of RNS in the kidney after CLP has never been examined, the protective effects of anti-inflammatory antioxidants in CLP suggest that oxidants may play a role in CLP-induced AKI (10,16).…”

mentioning

confidence: 98%

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Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

Wu¹,

Gökden²,

Mayeux³

2007

Journal of the American Society of Nephrology

123

133

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Acute kidney injury (AKI) remains a frequent and serious complication of human sepsis that contributes significantly to mortality. For better understanding of the development of AKI during sepsis, the cecal ligation and puncture (CLP) murine model of sepsis was studied using intravital video microscopy (IVVM) of the kidney. IVVM with FITC-dextran was used to determine the percentage of capillaries with continuous, intermittent or no flow at 0 (sham), 10, 16, and 22 h after CLP. There was a dramatic fall in capillary perfusion as early as 10 h after CLP that persisted through 22 h. The percentage of vessels with continuous flow at 16 h decreased from 73 ؎ 2% in shams to 16 ؎ 2% (P < 0.05), whereas the percentage of vessels with no flow increased from 4 ؎ 1% in shams to 42 ؎ 2% (P < 0.05). The capillary perfusion defect preceded the rise in serum creatinine. IVVM with dihydrorhodamine-123 was used to quantify in real time reactive nitrogen species (RNS) generation by renal tubules, and the inducible nitric oxide synthase inhibitor L-iminoethyl-lysine (mg/kg) was used to examine the role of inducible nitric oxide synthase inhibitor on capillary dysfunction and RNS generation. Tubular generation of RNS was significantly elevated at 10 h after CLP and was associated with tubules that were bordered by capillaries with reduced perfusion. L-Iminoethyl-lysine significantly reversed the capillary perfusion defect, blocked RNS generation, and reduced AKI. These data show that capillary dysfunction and RNS generation contribute to tubular injury and suggest that RNS should be considered a potential therapeutic target in the treatment of sepsis-induced AKI.

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 98%

Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

Wu¹,

Gökden²,

Mayeux³

2007

Journal of the American Society of Nephrology

123

133

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“…Moreover, recently it has been demonstrated that FP15, another ONOO Ϫ decomposition catalyst, also exerts vascular protective and anti-inflammatory effects in many models (Obrosova et al, 2005). Furthermore, ONOO Ϫ has been implicated in tissue damage, including the intestinal damage that accompanies endotoxic shock and has been detected in humans with sepsis (Fukuyama et al, 1997). Peroxynitrite can also cause DNA single-strand damage triggering poly(ADP-ribose) polymerase (PARP) activation, ultimately leading to cell death .…”

Section: Discussionmentioning

confidence: 99%

A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

Cuzzocrea¹,

Mazzon²,

Paola³

et al. 2006

J Pharmacol Exp Ther

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The aim of the present study was to assess the relative contributions of peroxynitrite formation following induction of nitric-oxide synthase (iNOS) in the pathophysiology of endotoxin-induced shock in the rat. To this end, we used a selective inhibitor of iNOS, N- (3-(aminomethyl)benzyl)acetamidine (1400W), and a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTTPs). Intravenous (i.v.) administration of Escherichia coli lipopolysaccharide (LPS; 4 mg/kg) elicited a timedependent fall in mean arterial pressure as well as liver, renal, and pancreatic tissue damage. 1400W (3-10 mg/kg i.v.) administered 30 min before LPS delayed the development of hypotension but did not improve survival. On the other hand, FeTTPs administered (10 -100 mg/kg i.v.) inhibited in a dose-dependent manner LPS-induced hypotension, tissue injury, and improved mortality rate. In separate experiments, rats were treated with LPS (4 mg/kg) or saline for control, and their aortas were isolated and placed in organ baths 2 h later. Tissues from LPS-treated rats had significant inhibition of contractile activity to phenylephrine as well as a significantly impaired relaxation response to acetylcholine. FeTPPs, when administered (100 mg/kg i.v.) 1 h before LPS, prevented the LPS-induced aortic contractile and endothelial dysfunction. These results demonstrate that nitric oxide-derived peroxynitrite formation plays an important role in this model of endotoxemia. Our results also suggest that use of an iNOS inhibitor in this setting has little beneficial effect in part because, in the presence of a failing eNOS system, some NO is needed to maintain adequate organ function.Severe hypotension, development of hyporeactivity to vasopressors, and ultimately, progressive multiple organ dysfunction characterize the pathogenesis of Gram-negative bacterial endotoxic shock (Siegel et al., 1967). The cause of the systemic vasodilation associated with shock, in particular, is still unclear, although overproduction of the potent vasodilator nitric oxide (NO) from the inducible form of nitric-oxide synthase (iNOS) has been implicated (Nathan, 1992;Thiemermann, 1994;Rixen et al., 1997). Even so, results from iNOS knockout mice have been controversial, with some studies reporting reduced endotoxin-related hypotension and others indicating no effects or even detrimental outcomes (Nicholson et al., 1999). Furthermore, the extensive evaluation of selective inhibitors for iNOS, such as aminoguanidine and N-iminoethyl-L-lysine in models of shock, have likewise been disappointing and controversial (Thiemermann et al., 1995;Parratt, 1997).In septic shock, inhibition of the activity of the constitutive endothelial cell isoform of nitric-oxide synthase (eNOS) precedes the induction of iNOS (Lu et al., 1996). Moreover, down-regulation of eNOS occurs at time points similar to those where iNOS induction is seen. Collectively, these results indicate that the beneficial effects of NO from eNOS are probably lost ...

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“…N itrated tyrosine residues (NT) have been used as a marker of the involvement of nitric oxide (NO) and its related chemistry in a number of pathophysiological disorders including cardiovascular (1, 2) neurodegenerative and malignant conditions (1)(2)(3)(4)(5), such as septic shock (6), multiple sclerosis (7), Alzheimer's disease (8), and amyotrophic lateral sclerosis (9). In cancer the presence of NT often correlates with a poor prognosis (10), suggesting diagnostic implications.…”

mentioning

confidence: 99%

Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation}{\mathrm{_{2}^{-}}}\end{equation}\end{document} reaction

Thomas

Espey

Vitek

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

176

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The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO ؊ ) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. nitrotyrosine ͉ nitric oxide ͉ peroxynitrite ͉ oxidation ͉ hemin N itrated tyrosine residues (NT) have been used as a marker of the involvement of nitric oxide (NO) and its related chemistry in a number of pathophysiological disorders including cardiovascular (1, 2) neurodegenerative and malignant conditions (1-5), such as septic shock (6), multiple sclerosis (7), Alzheimer's disease (8), and amyotrophic lateral sclerosis (9). In cancer the presence of NT often correlates with a poor prognosis (10), suggesting diagnostic implications.Several mechanisms for NT formation have been proposed, and its origin remains controversial (11-16). Detection of NT in vitro following exposure to synthetic peroxynitrite (ONOO Ϫ ) initially suggested that the reaction of NO with superoxide (O 2 Ϫ ) may be the primary source of NT (17,18). Further studies demonstrated that cogeneration of NO and O 2 Ϫ gave dissimilar results than bolus synthetic ONOO Ϫ (12,19,20). These disparities in nitration yields arose from further reactions of ONOO Ϫ with excess NO or O 2 Ϫ (21). Given the complexity of this seemingly simple reaction, much debate has ensued over the likelihood of NT formation under biologically relevant conditions (12,14).In addition to a ONOO Ϫ -mediated pathway, NT formation has been shown to result from the catalysis of nitrite oxidation by peroxidases, thus providing an alternate mechanism for its formation in vivo (22-24). Although leukocyte peroxidases likely account for a substantial amount of NT production in vivo, this mechanism fails to explain NT formation in the absence of inflammatory cells or peroxidases [i.e., a MPO Ϫ/Ϫ mouse model (25)].NT has been shown to occur on distinct proteins rather than in an indiscriminate manner (26). This may result from variations in protein susceptibility to nitration due to conformational differences or to association with redox active metals (27,28). We evaluated the relative efficacy of the synthetic ONOO Ϫ , NO͞O 2 Ϫ cogeneration, peroxidase, and redox active metal pathways to promote NT formation. Materials and MethodsBSA (essentially globulin-free), ribonuclease A, ferriprotoporphyrin IX (hemin), superoxide dismutase (SOD; bovine erythrocytes), cytochrome c, horseradish peroxidase (HRP), catalase (Cat), hypoxanthine (HX), myoglobin (horse heart), 2,2Ј-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), FeSO 4 , diethylenetriaminepentaacetic acid (DTPA), dimethylformamide (DMF), ␤-amyloid (1-42) protein (A␤), MnO 2 , and CuCl 2 were purchased from Sigma-Aldrich. H 2 O 2 , NaHCO 3 , NaNO 2 , and FeCl 3 were from Fisher Scientific....

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Clinical Evidence of Peroxynitrite Formation in Chronic Renal Failure Patients with Septic Shock

Cited by 175 publications

References 14 publications

Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock

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