Pulmonary Autoimmunity and Inflammation

Jeitner, Thomas M.; Lawrence, David A.

doi:10.1007/978-1-4615-4535-4_6

Cited by 4 publications

(5 citation statements)

References 110 publications

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“…HOCl and its conjugate base ClO-oxidize amino acids, peptides, proteins, and lipids [60][61][62][63] As mentioned before, MPO is expressed in neutrophils, monocytes, and some tissue macrophages, and generates HOCl during inflammation and infection. MPO is a key factor in cardiovascular, neurodegenerative, inflammatory, and immune-mediated diseases and catalyzes the reaction between physiologically present Cl-and hydrogen peroxide (H 2 O 2 ) to generate a potent oxidant, HOCl [57][58][59] (Figure 11). HOCl and its conjugate base ClO-oxidize amino acids, peptides, proteins, and lipids [60][61][62][63] and chlorinate nuclear bases in cellular DNA and RNA [60,64,65].…”

Section: Discussionmentioning

confidence: 99%

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Pietrofesa

Park

Mishra

et al. 2021

IJMS

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Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

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Section: Discussionmentioning

confidence: 99%

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Pietrofesa

Park

Mishra

et al. 2021

IJMS

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Section: Discussionmentioning

confidence: 99%

“…Hypochlorous acid has an enormous capacity to injure the brain and has been reviewed by Jeitner and Lawrence (2000). Glutathione (GSH) is the major defense against hypochlorous acid and chloramines, and its reaction with HOCl results in the production of predominantly of glutathione disulfide (GSSG) (Vissers and Winterbourn 1995;Carr and Winter-bourn 1997;Winterbourn and Brennan 1997;Pullar et al 1999) Cultured cells typically contain millimolar amounts of GSH and may account for the approximately 1000 fold greater amounts of HOCl that was required to inhibit cellular KGDHC activity than was used attenuate the activity of purified KGDHC activity (Figures 1-3).…”

Section: Ae)mentioning

confidence: 99%

Inhibition of the α‐ketoglutarate dehydrogenase complex by the myeloperoxidase products, hypochlorous acid and mono‐N‐chloramine

Jeitner

Gibson

2005

Journal of Neurochemistry

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a-Ketoglutarate dehydrogenase (KGDHC) complex activity is diminished in a number of neurodegenerative disorders and its diminution in Alzheimer Disease (AD) is thought to contribute to the major loss of cerebral energy metabolism that accompanies this disease. The loss of KGDHC activity appears to be predominantly due to post-translation modifications. Thiamine deficiency also results in decreased KGDHC activity and a selective neuronal loss. Recently, myeloperoxidase has been identified in the activated microglia of brains from AD patients and thiamine-deficient animals. Myeloperoxidase produces a powerful oxidant, hypochlorous acid that reacts with amines to form chloramines. The aim of this study was to investigate the ability of hypochlorous acid and chloramines to inhibit the activity of KGDHC activity as a first step towards investigating the role of myeloperoxidase in AD. Hypochlorous acid and mono-N-chloramine both inhibited purified and cellular KGDHC and the order of inhibition of the purified complex was hypochlorous acid (1·) > mono-Nchloramine ($50x) > hydrogen peroxide ($1 500). The inhibition of cellular KGDHC occurred with no significant loss of cellular viability at all exposure times that were examined. Thus, hypochlorous acid and chloramines have the potential to inactivate a major target in neurodegeneration.

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“…In physiological solutions, ACS are represented by molecules in oxidation states 0 and +1, namely, chlorine atoms (Cl • ), chlorine molecules (Cl 2 ), dichloro radical anions (

{Cl}_{2}^{• -}

) hypochlorous acid (HOCl) and hypochlorite anions (ClO − ), which are formed by the oxidation of chloride anion Cl − [1–7]. Among these ACS HOCl (ClO − ), a potent oxidant, can be produced in vivo by neutrophils containing activated myeloperoxidase which catalyzes the reaction between physiologically present chloride ions and hydrogen peroxide (H 2 O 2 ) [8]. In addition to neutrophils, eosinophils are also capable of generating HOCl, from H 2 O 2 and Cl − , by using eosinophil peroxidase.…”

Section: Introductionmentioning

confidence: 99%

Gamma-irradiation produces active chlorine species (ACS) in physiological solutions: Secoisolariciresinol diglucoside (SDG) scavenges ACS - A novel mechanism of DNA radioprotection

Mishra

Popov

Pietrofesa

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Secoisolariciresinol diglucoside (SDG), the main lignan in whole grain flaxseed, is a potent antioxidant and free radical scavenger with known radioprotective properties. However, the exact mechanism of SDG radioprotection is not well understood. The current study identified a novel mechanism of DNA radioprotection by SDG in physiological solutions by scavenging active chlorine species (ACS) and reducing chlorinated nucleobases. Methods The ACS scavenging activity of SDG was determined using two highly specific fluoroprobes: hypochlorite-specific 3′-(p-aminophenyl) fluorescein (APF) and hydroxyl radical-sensitive 3′-(p-hydroxyphenyl) fluorescein (HPF). Dopamine, an SDG structural analog, was used for proton 1H NMR studies to trap primary ACS radicals. Taurine N-chlorination was determined to demonstrate radiation-induced generation of hypochlorite, a secondary ACS. DNA protection was assessed by determining the extent of DNA fragmentation and plasmid DNA relaxation following exposure to ClO− and radiation. Purine base chlorination by ClO− and γ-radiation was determined by using 2-aminopurine (2-AP), a fluorescent analog of 6-aminopurine. Results: Chloride anions (Cl−) consumed >90% of hydroxyl radicals in physiological solutions produced by γ-radiation resulting in ACS formation, which was detected by 1H NMR. Importantly, SDG scavenged hypochlorite- and γ-radiation-induced ACS. In addition, SDG blunted ACS-induced fragmentation of calf thymus DNA and plasmid DNA relaxation. SDG treatment before or after ACS exposure decreased the ClO− or γ-radiation-induced chlorination of 2-AP. Exposure to γ-radiation resulted in increased taurine chlorination, indicative of ClO− generation. NMR studies revealed formation of primary ACS radicals (chlorine atoms (Cl•) and dichloro radical anions (Cl2−•)), which were trapped by SDG and its structural analog dopamine. Conclusion We demonstrate that γ-radiation induces the generation of ACS in physiological solutions. SDG treatment scavenged ACS and prevented ACS-induced DNA damage and chlorination of 2-aminopurine. This study identified a novel and unique mechanism of SDG radioprotection, through ACS scavenging, and supports the potential usefulness of SDG as a radioprotector and mitigator for radiation exposure as part of cancer therapy or accidental exposure.

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Pulmonary Autoimmunity and Inflammation

Cited by 4 publications

References 110 publications

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Inhibition of the α‐ketoglutarate dehydrogenase complex by the myeloperoxidase products, hypochlorous acid and mono‐N‐chloramine

Gamma-irradiation produces active chlorine species (ACS) in physiological solutions: Secoisolariciresinol diglucoside (SDG) scavenges ACS - A novel mechanism of DNA radioprotection

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