The lactoperoxidase system links anion transport to host defense in cystic fibrosis

Conner, Gregory E.; Wijkstrom-Frei, Corinne; Randell, Scott H.; Fernandez, Vania E.; Salathé, Matthias

doi:10.1016/j.febslet.2006.12.025

Cited by 112 publications

(120 citation statements)

References 48 publications

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“…In our setting, the H 2 O 2 /LPO system is unlikely to have a role based on the following observations. First, LPO is not secreted from in vitro cultured AECs [44] and all the studies that previously demonstrated an LPO-dependent antimicrobial function required the addition of LPO in the experiments [38,39,43]. However, here we observe an antiviral effect of DUOX2 without the ectopic addition of LPO.…”

Section: Rsv Interferes With the Expression Of Duox2contrasting

confidence: 46%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2-and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H 2 O 2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

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Section: Rsv Interferes With the Expression Of Duox2contrasting

confidence: 46%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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“…This transepithelial movement results in 460 M SCN Ϫ in the airway secretions, substantially higher than the plasma concentration (24). SCN Ϫ release is absent in the epithelial cells missing CFTR activity (25,26 (Fig. 1A) (27).…”

mentioning

confidence: 99%

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

Szép

Lü

2009

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

125

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Cystic fibrosis (CF) is a pleiotropic disease, originating from mutations in the CF transmembrane conductance regulator (CFTR). Lung injuries inflicted by recurring infection and excessive inflammation cause Ϸ90% of the morbidity and mortality of CF patients. It remains unclear how CFTR mutations lead to lung illness. Although commonly known as a Cl ؊ channel, CFTR also conducts thiocyanate (SCN ؊ ) ions, important because, in several ways, they can limit potentially harmful accumulations of hydrogen peroxide (H 2O2) and hypochlorite (OCl ؊ ). First, lactoperoxidase (LPO) in the airways catalyzes oxidation of SCN ؊ to tissue-innocuous hypothiocyanite (OSCN ؊ ), while consuming H2O2. Second, SCN ؊ even at low concentrations competes effectively with Cl ؊ for myeloperoxidase (MPO) (which is released by white blood cells), thus limiting OCl ؊ production by the enzyme. Third, SCN ؊ can rapidly reduce OCl ؊ without catalysis. Here, we show that SCN ؊ and LPO protect a lung cell line from injuries caused by H 2O2; and that SCN ؊ protects from OCl ؊ made by MPO. Of relevance to inflammation in other diseases, we find that in three other tested cell types (arterial endothelial cells, a neuronal cell line, and a pancreatic ␤ cell line) SCN ؊ at concentrations of >100 M greatly attenuates the cytotoxicity of MPO. Humans naturally derive SCN ؊ from edible plants, and plasma SCN ؊ levels of the general population vary from 10 to 140 M. Our findings raise the possibility that insufficient levels of antioxidant SCN ؊ provide inadequate protection from OCl ؊ , thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis, neurodegeneration, and certain cancers.hydrogen peroxide ͉ hypochlorite ͉ hypothiocyanite ͉ lactoperoxidase ͉ myeloperoxidase

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“…The excited TBA -molecule undergoes decomposition by eorganization to give SCN -as a photo product. Thiocyanate 26 is known to be an important part in the biosynthesis of hypothiocyanite by a lactoperoxidase [27][28][29] . Thus the complete absence of thiocyanate in the human body is damaging to the human host defense system.…”

Section: Resultsmentioning

confidence: 99%

Photoinduced Electron Transfer Reaction of 2-Thiobarbituric Acid and Methylene Blue: Mechanism and Kinetics

2013

Chem Sci Trans

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Abstract:Barbiturates are known to have hypnotic properties and are used as active moiety on central nervous system. Depends up on the experiments conditions and functional group present on the drugs, make the drugs labile to photodecomposition. The photosensitized reaction of 2-thiobarbituric acid (2TBA) with methylene blue (MB) in alkaline medium using visible light has been studied. 2TBA exists in protonated and deprotonated form in equilibrium in alkaline medium. Photosensitized electron transfer from the deprotonated 2TBA to excited state MB takes place and the energy is transferred to 2TBA molecule which undergoes chemical reaction. The interconversion of protonated form to deprotonated form during the reaction is observed. The rate of the reaction has been calculated and the effect of pH, concentration of the sensitizer, the light intensity on the rate of the reaction has been studied. The quantum efficiency of the photo chemical reaction is calculated using potassium ferrioxalate actinometer and the effect of the concentration of the substrate on the quantum efficiency is calculated. The reaction mechanism and the excited states involved have been suggested.

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The lactoperoxidase system links anion transport to host defense in cystic fibrosis

Cited by 112 publications

References 48 publications

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

Photoinduced Electron Transfer Reaction of 2-Thiobarbituric Acid and Methylene Blue: Mechanism and Kinetics

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