Effects of Peroxynitrite on Pulmonary Edema and the Oxidative State (original) (raw)
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Nitric oxide and peroxynitrite-mediated pulmonary cell death
The American journal of physiology, 1998
Nitric oxide (.NO) can be produced within the lung, and recently inhaled nitric oxide has been used as a therapeutic agent. Peroxynitrite1 (ONOO-), the product of the nearly diffusion-limited reaction between .NO and superoxide, may represent the proximal reactive species mediating .NO injury to pulmonary cells. To investigate the physiological and pathological reactivities of .NO and ONOO- at the molecular and cellular levels, bovine pulmonary artery endothelial cells (BPAEC) and rat type II epithelial cells were exposed to .NO (0.01-2.5 microM/min for 2 h) generated by spermine-NONOate and papa-NONOate and to the same fluxes of ONOO- generated by 1,3-morpholinosydnonimine (SIN-1). Exposure to SIN-1 resulted in cellular injury and death in both cell types. Epithelial cells displayed a concentration-dependent loss of cellular viability within 8 h of exposure. In contrast, BPAEC loss of cellular viability was evident after 18 h postexposure. Events preceding cell death in BPAEC inclu...
Evidence for in vivo peroxynitrite production in human acute lung injury
1995
During inflammation nitric oxide reacts at near diffusion limited rates with superoxide to form the strong oxidant peroxynitrite. Nitration on the or-rho position is a major product of peroxynitrite attack on proteins. In the present study we investigated whether immunohistochemical detection of nitrotyrosine (footprint of peroxynitrite) can be associated with human hepatitrs. Paraffin-embedded liver tissue biopsies from patients with chronic active hepatitis, chronic active hepatitis plus cirrhosis and chronic persistent hepatitis exhibit significant specific immunostaining with the antibody to nitrotyrosine. Positive staining was found in 57% and 72% of tissue specimens from patients with chronic hepatitis and cirrhosis, respectively. lmmunohistochemical staining of nitrotyrosine residues was found in the hepatocytes and Kuppffer cells of the necrotic area. The presence of nitrotyrosine indicates that oxidants derived from nitric oxide such as peroxynitrite are generated in human hepatitis and may be involved in its pathogenesis. 0 1998 Elsevier Science Inc.
CARDIOVASCULAR EFFECTS OF PEROXYNITRITE
Clinical and Experimental Pharmacology and Physiology, 2007
both exist as free radicals. By itself, PN is not a free radical, but it can generate nitrogen dioxide (·NO 2 ) and carbonate radical ( ·) upon reaction with CO 2 . 2. The reaction of CO 2 constitutes a major pathway for the disposition of PN produced in vivo and this is based on the rapid reaction of PN anion with CO 2 and the availability of CO 2 in both intra-and extracellular fluids. The free radicals ·NO 2 and ·, in combination with ·NO, generated from nitric oxide synthase, can bring about oxidation of critical biological targets resulting in tissue injury. However, the reactions of ·NO 2 , · and ·NO with carbohydrates, protein and non-protein thiols, phenols, indoles and uric acid could result in the formation of a number of nitration and nitrosation products in the vasculature. These products serve as long-acting ·NO donors and, therefore, contribute to vasorelaxant properties, protective effects on the heart, inhibition of leucocyte-endothelial cell interactions and reduction of reperfusion injury.
Reaction of Superoxide and Nitric Oxide with Peroxynitrite
Journal of Biological Chemistry, 2001
Peroxynitrite (ONOO ؊ /ONOOH), the product of the diffusion-limited reaction of nitric oxide (⅐ NO) with superoxide (O 2 .), has been implicated as an important mediator of tissue injury during conditions associated with enhanced ⅐ NO and O 2. production. Although several groups of investigators have demonstrated substantial oxidizing and cytotoxic activities of chemically synthesized peroxynitrite, others have proposed that the relative rates of ⅐ NO and production may be critical in determining the reactivity of peroxynitrite formed in situ (Miles, A. M.
Peroxynitrite: A two-faced metabolite of nitric oxide
Life Sciences, 1997
The discovery that nitric oxide (NO) reacts with superoxide (O2.-) forming peroxynitrite (ONOO-) (1) and the proof that this reaction occurs in vivo (2,3) holds enormous implications for the understanding of free radicals in biological systems. Not only in mammalian defense mechanisms against microorganisms, but also in pathophysiology during overexposure of tissues to radicals or other highly reactive species. Peroxynitrite is a highly reactive compound with harmful effects on cells and could therefore be an important microbicidal compound. Furthermore, the reaction of superoxide with NO interferes with NO signalling mechanisms. NO is not only released in response to inflammatory agents by inflammatory cells, but is also an important messenger molecule in paracrine mechanisms and neurotransmission. Whether peroxynitrite formation is a negative side effect of NO and superoxide release, or a functional characteristic is yet to be determined, and will be discussed in this review.
Nitric oxide and peroxynitrite in health and disease
Physiological reviews
The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
British Journal of Pharmacology, 1997
1. Peroxynitrite is a toxic oxidant species produced from nitric oxide (NO) and superoxide. We have recently observed that the cell-permeable superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) inhibits the suppression of mitochondrial respiration elicited by authentic peroxynitrite in vitro. Here we have investigated the relative potency of MnTBAP and a range of related compounds in terms of inhibition of peroxynitrite-induced oxidation and cytotoxicity. In addition, we tested the effects of MnTBAP on the vascular and the cellular energetic failure in rodent models of endotoxic shock. 2. We observed a dose-related inhibition of the peroxynitrite-induced oxidation of dihydrorhodamine 123 to rhodamine by MnTBAP, ZnTBAP and FeTBAP, but not by MnTMPyP [(5,10,15,20-tetrakis(N-methyl-4'-pirydyl)porphinato)-mangan ese (III)]. In addition, MnTBAP, ZnTBAP and FeTBAP, but not MnTMPyP prevented the suppression of mitochondrial respiration by authentic peroxynitrite in cultured J774 macrophages. 3. In rat cultured aortic smooth muscle cells, MnTBAP protected against the suppression of mitochondrial respiration in response to authentic peroxynitrite, immunostimulation and nitric oxide (NO) donor compounds. MnTBAP slightly reduced the amount of nitrite/nitrate produced in response to immunostimulation in these cells. 4. Administration of MnTBAP, 15 mg kg-1 i.v., before the administration of endotoxin (15 mg kg-1, i.v.) to rats ameliorated the development of vascular hyporeactivity and the development of endothelial dysfunction in the thoracic aorta ex vivo. 5. MnTBAP also prevented the endotoxin-induced decrease in mitochondrial respiration, the development of DNA single strand breaks, and the depletion of intracellular NAD+ in peritoneal macrophages ex vivo. 6. MnTBAP did not inhibit the expression by endotoxin of the inducible NO synthase in lung samples. 7. MnTBAP did not alter survival rate in mice challenged with high dose endotoxin. 8. Our findings, taken together with previous data demonstrating protective effects of NO synthase inhibitors against the endotoxin-induced contractile and energetic failure in the models of shock used in the current study, and with the known ability of peroxynitrite to cause cellular energy depletion, suggest a role for peroxynitrite in the pathogenesis of cellular energetic failure and contractile dysfunction in endotoxin shock.
Archives of Toxicology, 2002
Nitric oxide (NO) is an environmental pollutant found in smog and cigarette smoke. Recently, NO has been discovered to act as a molecular messenger, mediating various physiological functions. However, when an excess of NO is present, cytotoxic and mutagenic effects can also be induced. The reaction of NO with superoxide results in the formation of peroxynitrite (ONOO(-)), which decomposes into the hydroxyl radical and nitrogen dioxide. Both of them are potent oxidant species that may initiate and propagate lipid peroxidation. In the present study, we examined the effects of NO and ONOO(-) on the induction of lipid peroxidation and cell death mechanisms in rats and in A549 pulmonary epithelial cells. The results showed that ONOO(-) is able to induce lipid peroxidation in pulmonary epithelial cells in a dose-dependent manner. 8-Epi-prostaglandin F(2)(alpha) can serve as a good biomarker of lipid peroxidation both in vitro and in vivo. Postmitotic apoptosis was found in A549 cells exposed to NO, whereas ONOO(-) induced cell death more characteristic of necrosis than apoptosis. Apoptosis that occurred in cells may be related to the dysfunction of mitochondria, the release of cytochrome c into cytosol, and the activation of caspase-9. The relationship between caspase activation and the cleavage of other death substrates during postmitotic apoptosis in A549 cells needs further investigation.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2005
Objective-Peroxynitrite, a potent oxidant generated by the reaction of NO with superoxide, has been implicated in the promotion of atherosclerosis. We designed this study to determine whether peroxynitrite induces its proatherogenic effects through induction of endoplasmic reticulum (ER) stress. Methods and Results-Human vascular endothelial cells treated with Sin-1, a peroxynitrite generator, induced the expression of the ER chaperones GRP78 and GRP94 and increased eIF2␣ phosphorylation. These effects were inhibited by the peroxynitrite scavenger uric acid. Sin-1 caused the depletion of ER-Ca 2ϩ , an effect known to induce ER stress, resulting in the elevation of cytosolic Ca 2ϩ and programmed cell death (PCD). Sin-1 treatment was also found, via 3-nitrotyrosine and GRP78 colocalization, to act directly on the ER. Adenoviral-mediated overexpression of GRP78 in endothelial cells prevented Sin-1-induced PCD. Consistent with these in vitro findings, 3-nitrotyrosine was observed and colocalized with GRP78 in endothelial cells of early atherosclerotic lesions from apolipoprotein E-deficient mice. Conclusions-Peroxynitrite is an ER stress-inducing agent. Its effects include the depletion of ER-Ca 2ϩ , a known mechanism of ER stress induction. The observation that 3-nitrotyrosine-containing proteins colocalize with markers of ER stress within early atherosclerotic lesions suggests that peroxynitrite contributes to atherogenesis through a mechanism involving ER stress. (Arterioscler Thromb Vasc Biol. 2005;25:2623-2629.)