Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis

Behr, Jürgen; Degenkolb, Barbara; Maier, Konrad; Braun, B.; Beinert, T.; Krombach, Fritz; Vogelmeier, Claus; Fruhmann, G

doi:10.1183/09031936.95.08081286

Cited by 57 publications

(57 citation statements)

References 32 publications

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“…For example, patients with IPF have decreased levels of reduced glutathione in the epithelial lining fluid of their lungs (19)(20)(21)(22). Several studies suggest that a number of antioxidant and detoxification enzymes are elevated in inflammatory and/or granulomatous interstitial lung diseases and in areas of epithelial regeneration; however, they are low/ absent in the fibrotic lesions of IPF lungs.…”

Section: Oxidant-antioxidant Imbalance In Ipfmentioning

confidence: 99%

Oxidative Stress in Pulmonary Fibrosis

Kinnula

Fattman

Tan

et al. 2005

Am J Respir Crit Care Med

377

132

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Idiopathic ulmonary fibrosis (histopathology of usual interstitial pneumonia) is a progressive lung disease of unknown etiology. No treatment has been shown to improve the prognosis of the patients with this disease. Recent evidence, including the observations that the patients with idiopathic pulmonary fibrosis have higher levels of oxidant stress than control patients, and a recent multicenter European study examining the effect of the antioxidant N-acetylcysteine on the progression of idiopathic pulmonary fibrosis suggest that the cellular redox state may play a significant role in the progression of this disease. These complex mechanisms include activation of growth factors as well as regulation of matrix metalloproteinases and protease inhibitors. Potential future approaches for the therapy of interstitial pulmonary fibrosis may involve synthetic agents able to modulate cellular redox state. Investigation into therapeutic approaches to inhibit oxidant-mediated reactions in the initiation and progression of pulmonary fibrosis may provide hope for the future treatment of this disease.Keywords: antioxidant; idiopathic pulmonary fibrosis; oxidant; radical Idiopathic pulmonary fibrosis (IPF) is a prototype of idiopathic interstitial pneumonias, a chronic disease of the lung parenchyma that leads to diffuse scarring and end-stage tissue fibrosis (1). Typical features in this disease include dyspnea, diffuse interstitial infiltrates, progressive lung fibrosis, and poor prognosis. The pathologic changes in IPF include patchy fibrotic lesions that vary both in age and activity, and only weak inflammation. The focal zones of fibroblast proliferation are called "fibroblastic foci" and appear to occur at sites of recent alveolar injury (1, 2). The biochemical mechanisms in the pathogenesis of IPF are still poorly understood and medical therapies have thus far offered little if any benefit against the progression of this disease (1,3,4).As the name implies, there is no known etiologic stimulus that initiates this disease. Current evidence suggests that both endogenous and exogenous stimuli may injure the alveolar epithelium. This is followed by an abnormal repair process in individuals unable to effectively heal the damage. The majority of the original articles and reviews on IPF have focused on the (Received in original form January 5, 2005; accepted in final form May 3, 2005) This and the original studies of V.L.K.

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Section: Oxidant-antioxidant Imbalance In Ipfmentioning

confidence: 99%

Oxidative Stress in Pulmonary Fibrosis

Kinnula

Fattman

Tan

et al. 2005

Am J Respir Crit Care Med

377

132

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“…RTLF dilution by commonly performed lavage procedures has been estimated to be about 100-fold, and lower RTLF (ELF) concentrations of GSH have been reported to be in the range of 100 to 500 pM (135,144,159). Extrapolation of this dilution to reported ascorbate and urate concentrations would yield lower RTLF ascorbate levels of 50 to 180 pM and urate levels of 30 to 130 pM, i.e., similar to or lower than in plasma (Table 3).…”

Section: Respiratory Tract Lining Fluidsmentioning

confidence: 99%

Oxidative stress and antioxidants at biosurfaces: plants, skin, and respiratory tract surfaces.

Cross

Vliet

Louie

et al. 1998

Environ Health Perspect

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Atmospheric pollutants represent an important source of oxidative and nitrosative stress to both terrestrial plants and to animals. The exposed biosurfaces of plants and animals are directly exposed to these pollutant stresses. Not surprisingly, living organisms have developed complex integrated extracellular and intracellular defense systems against stresses related to reactive oxygen and nitrogen species (ROS, RNS), including 03 and NO2. Plant and animal epithelial surfaces and respiratory tract surfaces contain antioxidants that would be expected to provide defense against environmental stress caused by ambient ROS and RNS, thus ameliorating their injurious effects on more delicate underlying cellular constituents. Parallelisms among these surfaces with regard to their antioxidant constituents and environmental oxidants are presented. The reactive substances at these biosurfaces not only represent an important protective system against oxidizing environments, but products of their reactions with ROS/RNS may also serve as biomarkers of environmental oxidative stress. Moreover, the reaction products may also induce injury to underlying cells or cause cell activation, resulting in production of proinflammatory substances including cytokines. In this review we discuss antioxidant defense systems against environmental toxins in plant cell wall/apoplastic fluids, dead keratinized cells/interstitial fluids of stratum corneum (the outermost skin layer), and mucus/respiratory tract lining fluids.-Environ Health Perspect 1 06(Suppl 5): 1241-1251 (1998 The aim of this review is to highlight certain parallels between the antioxidant mechanisms responsible for protecting diverse environmentally exposed biosurfaces. Although there are numerous other environmental oxidants that contribute to surface oxidative stress (e.g., oxides of nitrogen, cigarette smoke, radiation), our focus will be on 03 as a representative environmental oxidant and on the antioxidants with which it can be expected to react at plant, skin, and respiratory tract surfaces. Although in most circumstances the oxidant can be expected to be neutralized, products of reactions with constituents of the extracellular fluids, e.g., cytotoxic aldehydes produced by reactions of 03 with extracellular lipids (12-14), may be largely responsible for cell or tissue injury by environmental toxins. Structural ConsiderationsThe similarities of the interfaces between the environment and plant and animal tissues are simplistically depicted in Figure 1. In plants, uptake of environmental toxins can be expected to occur mainly at the cell wall surface and, via the stomata, within the extracellular apoplastic fluids (15-17). The skin and the respiratory tract are the animal organs most direcdy exposed to oxidant air pollutants. Although numerous studies have documented the effects of oxidants on lungs, and have to some extent directed attention to the importance of the respiratory tract lining fluids (RTLFs) (18)(19)(20)(21)(22), only a few studies have described possible oxi...

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“…The GSHt concentration of the BALF and the bronchoalveolar cell lysate sample was calculated using an internal standard of 0.84 mM GSH [24]. The GSHt content of BAL cells is expressed as nmol?mg protein -1 .…”

Section: Glutathione Concentration and Formmentioning

confidence: 99%

Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers

Neurohr

Lenz²,

Ding³

et al. 2003

Eur Respir J

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The antioxidant glutathione (GSH) is increased in the epithelial lining fluid (ELF) of chronic smokers. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), also known as c-glutamylcysteine synthetase, consisting of a heavy, catalytic (GCLC) and a light, modulatory (GCLM) subunit.To determine the contribution of bronchoalveolar lavage (BAL) cells to GSH levels in ELF, BAL was performed in eight smokers and eight never-smokers. Intra-and extracellular total glutathione (GSHt) levels and GCL subunit expression were assessed.GSHt was increased in ELF from smokers (1,090.1¡163.0 mM versus 559.2¡ 48.2 mM). GSHt content of BAL cells (nmol?mg protein -1 ) was decreased in smokers without differences reaching statistical significance (8.0¡1.4 versus 12.4¡2.6). GCLM expression was also reduced in smokers (0.6¡0.1 versus 2.8¡0.4) and correlated with intracellular GSHt content. There was no significant difference in GCLC expression and in differential cell counts in BAL fluid.The authors conclude that smoking does increase glutathione levels in the epithelial lining fluid but not intracellular levels in bronchoalveolar lavage cells. The data suggest that the intracellular glutathione concentration of bronchoalveolar lavage cells (predominately alveolar macrophages) is regulated by the modulatory glutamatecysteine ligase subunit rather than the catalytic subunit. Eur Respir J 2003; 22: 82-87.

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Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis

Cited by 57 publications

References 32 publications

Oxidative Stress in Pulmonary Fibrosis

Oxidative Stress in Pulmonary Fibrosis

Oxidative stress and antioxidants at biosurfaces: plants, skin, and respiratory tract surfaces.

Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers

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