Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the role of red blood cell (RBC) antioxidants as clinical markers of oxidative exposure, we measured RBC glutathione (GSH) concentrations in 32 adult patients with cystic fibrosis (CF), and 8 healthy age-matched control subjects. We chose patients with CF because this disease is characterized by severe bronchial inflammation and marked oxidant-antioxidant imbalance. Although the GSH concentration of the two study groups was not significantly different, the RBC GSH concentration of patients with CF had a greater variability (p = 0.01) and was also inversely and significantly correlated to tests of pulmonary function (p < 0.05). These data indicate a large and significant interindividual variability of erythrocytic antioxidants in patients with CF, with a compensatory, but probably inadequate, increase in patients with more severe respiratory deterioration. Red blood cell GSH concentration may thus provide a biologic marker for disease severity and a rationale for antioxidant manipulation in these patients.
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PMID:Erythrocytic glutathione in cystic fibrosis. A possible marker of pulmonary dysfunction. 818 40

Glutathione (GSH) is a potentially important component of antioxidant defense in the epithelial lung lining fluid. Cystic fibrosis (CF) patients have chronic inflammation in which oxidative stress can be a factor. To examine the hypothesis that the transport of GSH content was defective in CF patients, intracellular and extracellular GSH were measured by HPLC. Four cell lines were used: CFT1 cells [with defective CF transmembrane conductance regulator (CFTR), DeltaF508 homozygous, two clones] and one of the CFT1 clones transfected with either normal CFTR (CFTR repleted) or beta-galactosidase. GSH content in the apical fluid was 55% lower in CFTR-deficient cultures than in CFTR-repleted cells (P < 0.001). In contrast, intracellular GSH content was similar in CFT1 cells and CFTR-repleted cells. gamma-Glutamyl transpeptidase activity, which degrades extracellular GSH, did not account for differences in apical GSH. Rather, GSH efflux of CFTR-deficient cells was lower than that of CFTR-repleted cells. These studies suggested that decreased GSH content in the apical fluid in CF resulted from abnormal GSH transport associated with a defective CFTR.
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PMID:Abnormal glutathione transport in cystic fibrosis airway epithelia. 1040 37

Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified, since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered (600 mg twice daily for 3 days) to seven patients with CF. ELF total, reduced, and oxidized GSH increased (P < 0.05, all compared with before GSH therapy), suggesting adequate RES delivery and utilization of GSH. Phorbol 12-myristate 13-acetate-stimulated superoxide anion (O2-.) release by ELF inflammatory cells decreased after GSH therapy (P < 0.002). This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O2-. release (P < 0.001). No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF and support the rationale for further clinical evaluation.
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PMID:Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. 1040 5

Oxidative stress is implicated in the pathology of numerous diseases of the lung. These include cystic fibrosis, chronic obstructive airway disease and asthma. All these conditions are characterised by an imbalance between the amounts of reactive oxygen species (ROS) and available antioxidant defences. In the lung, ROS arise from endogenous sources, such as the influx of inflammatory cells or exogenous sources, such as from air pollution and cigarette smoke. When ROS production increases the redox balance of the airways alters, and this can lead to bronchial hyperactivity and further inflammation. The lung, like many other tissues, has a range of antioxidant defences which help to maintain a balanced redox status. These antioxidants are present in the intracellular, the vascular and extracellular respiratory tract lining fluid (RTLF) compartments. The reduced glutathione (GSH) content of RTLF is particularly high and new findings are beginning to reveal the role that the RTLF GSH pool plays in defending the lung.
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PMID:Gluthathione: in defence of the lung. 1054 51

Several studies have demonstrated ongoing oxidative stress in cystic fibrosis (CF). With the complexity of the antioxidant network, measurement of individual antioxidants does not necessarily assess how they work in combination. One measure that has been proposed as a gauge of total plasma antioxidant capacity is the Trolox-equivalent antioxidant capacity (TEAC) of plasma. We decided to look at plasma TEAC levels in children with CF, and relate this measure to their nutritional status, lung function, and blood measurements of several known antioxidants. We hypothesized that values in general would be lower than healthy control values, especially during acute pulmonary exacerbations. Twenty-nine children were evaluated, five of whom were during an acute pulmonary exacerbation. Height and weight, expiratory spirometry, and lung volumes were assessed, as were serum concentrations of vitamins A and E, uric acid, albumin, and lymphocyte glutathione (GSH) concentrations. TEAC values for nonhospitalized patients (1.40 +/- 0. 20 mmol/L) were not different from laboratory control values (1.35 +/- 0.11 mmol/L), but greater than values for hospitalized patients (1.09 +/- 0.17 mmol/L). TEAC correlated with anthropometric values (height: r = 0.39, P < 0.03; weight: r = 0.50, P < 0.01; body mass index: r = 0.47, P < 0.01), and pulmonary function (forced expiratory volume in 1 sec: r = 0.43, P < 0.02; residual volume/total lung capacity: r = -0.42, P < 0.03), but not with age. Univariate correlation with blood measurements demonstrated a significant correlation of TEAC with uric acid (r = 0.49, P < 0.02), but not with albumin, vitamins A or E, or lymphocyte GSH. Multiple regression analysis demonstrated a correlation between TEAC and uric acid, albumin, and lymphocyte GSH in the non-hospitalized group (r(2) = 0.38, P < 0.03). We conclude that TEAC appears to represent a mixed antioxidant response, rather than response to a single antioxidant. While being responsive to oxidative stress, the mechanism of the response may differ between clinical situations, such that the clinical significance of changes in plasma TEAC remains to be defined.
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PMID:Total plasma antioxidant capacity in cystic fibrosis. 1063 97

Mutations in the cystic fibrosis gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) lead to altered chloride (Cl(-)) flux in affected epithelial tissues. CFTR is a Cl(-) channel that is regulated by phosphorylation, nucleotide binding, and hydrolysis. However, the molecular basis for the functional regulation of wild type and mutant CFTR remains poorly understood. CFTR possesses two nucleotide binding domains, a phosphorylation-dependent regulatory domain, and two transmembrane domains that comprise the pore through which Cl(-) permeates. Mutations of residues lining the channel pore (e.g. R347D) are typically thought to cause disease by altering the interaction of Cl(-) with the pore. However, in the present study we show that the R347D mutation and diphenylamine-2-carboxylate (an open pore inhibitor) also inhibit CFTR ATPase activity, revealing a novel mechanism for cross-talk from the pore to the catalytic domains. In both cases, the reduction in ATPase correlates with a decrease in nucleotide turnover rather than affinity. Finally, we demonstrate that glutathione (GSH) inhibits CFTR ATPase and that this inhibition is altered in the CFTR-R347D variant. These findings suggest that cross-talk between the pore and nucleotide binding domains of CFTR may be important in the in vivo regulation of CFTR in health and disease.
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PMID:Perturbation of the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) inhibits its atpase activity. 1112 65

Though the cause of cystic fibrosis (CF) pathology is understood to be the mutation of the CFTR protein, it has been difficult to trace the exact mechanisms by which the pathology arises and progresses from the mutation. Recent research findings have noted that the CFTR channel is not only permeant to chloride anions, but other, larger organic anions, including reduced glutathione (GSH). This explains the longstanding finding of extracellular GSH deficit and dramatically reduced extracellular GSH:GSSG (glutathione disulfide) ratio found to be chronic and progressive in CF patients. Given the vital role of GSH as an antioxidant, a mucolytic, and a regulator of inflammation, immune response, and cell viability via its redox status in the human body, it is reasonable to hypothesize that this condition plays some role in the pathogenesis of CF. This hypothesis is advanced by comparing the literature on pathological phenomena associated with GSH deficiency to the literature documenting CF pathology, with striking similarities noted. Several puzzling hallmarks of CF pathology, including reduced exhaled NO, exaggerated inflammation with decreased immunocompetence, increased mucus viscoelasticity, and lack of appropriate apoptosis by infected epithelial cells, are better understood when abnormal GSH transport from epithelia (those without anion channels redundant to the CFTR at the apical surface) is added as an additional explanatory factor. Such epithelia should have normal levels of total glutathione (though perhaps with diminished GSH:GSSG ratio in the cytosol), but impaired GSH transport due to CFTR mutation should lead to progressive extracellular deficit of both total glutathione and GSH, and, hypothetically, GSH:GSSG ratio alteration or even total glutathione deficit in cells with redundant anion channels, such as leukocytes, lymphocytes, erythrocytes, and hepatocytes. Therapeutic implications, including alternative methods of GSH augmentation, are discussed.
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PMID:Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. 1139 Jan 89

Recent studies suggest that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein modulates epithelial reduced glutathione (GSH) transport and when defective creates an antioxidant imbalance. To test whether the CFTR protein modulates lung antioxidant defenses in vivo, epithelial lining fluid (ELF) and lung tissue from CFTR knockout (CFTR-KO) and wild-type (WT) mice were compared for GSH content and the activities of glutathione reductase, glutathione peroxidase, and gamma-glutamyltransferase. In the CFTR-KO mice, the ELF concentration of GSH was decreased (51%) compared with that in WT mice. The concentration of GSH in the lung tissue of CFTR-KO mice, however, was not significantly different from that in WT mice. The activities of glutathione reductase and glutathione peroxidase in the lung tissue of CFTR-KO mice were significantly increased compared with those in WT mice (48 and 28%, respectively). Tissue lipid and DNA oxidation were evaluated by measurement of thiobarbituric acid-reactive substances and 8-hydroxy-2'-deoxyguanosine, respectively. The levels of thiobarbituric acid-reactive substances and 8-hydroxy-2'-deoxyguanosine in the lung tissue of CFTR-KO mice were significantly increased compared with those in WT mice. These data support our hypothesis that a mutation in the CFTR gene can affect the antioxidant defenses in the lung and may contribute to the exaggerated inflammatory response observed in CF.
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PMID:Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. 1140 42

Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. While the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is restricted to the biliary epithelium in the liver, recent findings indicate that CFTR modulates reduced glutathione (GSH) transport and that CFTR dysfunction creates an imbalance in the antioxidant defense. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. Because oxidative injury contributes to the development of liver disease, we hypothesized that 2 members of the GST superfamily, GSTM1 and GSTP1, which are expressed in the biliary epithelium, could influence the hepatic status in patients with CF. The potential impact of GSTM1 and GSTP1 gene polymorphisms was assessed in 106 children with CF (mean age, 11.5 years). Based on polymerase chain reaction/restriction fragment length polymorphism analysis, we found that the frequency of GSTP1-Ile(105)/Ile(105) genotype was significantly higher in patients with CF with liver disease than in those without (P <.03). Among the youngest patients, aged 6 years, GSTP1-Ile(105)/Ile(105) genotype was associated with a 8-fold increase in the risk of liver disease compared with other GSTP1 genotypes (P =.002). No association between the GSTM1 genotype and liver status was documented. In conclusion, GSTP1-Ile(105)-encoding allele contributes to hepatic dysfunction in CF. Identification of this polymorphism may have prognostic value and prompt early treatment in patients with CF with an increased risk of liver disease.
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PMID:Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. 1260 71

Glutathione (GSH) is an important component of antioxidant defenses in airway surface liquid (ASL), a thin layer (10-30 microm) of liquid covering the epithelial cells lining the airways of the lung. Decreased levels of ASL GSH have been reported in cystic fibrosis (CF), potentially contributing to the severe oxidative stress seen in this disease. To help investigate the role of GSH in ASL, we developed a technique suitable for analysis of GSH and its oxidized form (GSSG) in microliter samples using capillary sampling followed by capillary zone electrophoresis (CZE) analysis with conductivity detection. CZE was carried out in 100 mM CHES and 40 mM lithium hydroxide with 5 mM spermine at pH 9.1 under an applied electric field of -416 V cm(-1). To prevent any autooxidation of GSH during sample manipulations, the samples were treated with N-ethylmaleimide (50 mM) to alkylate free thiol (-SH). Under these conditions, GSH and GSSG were cleanly separated without interference from common anions (e.g. Cl(-), PO(4)(3-), HCO(3)(-), etc.) and the limit of detection for ASL analysis was 11 microM for GSH and 8 microM for GSSG (S/N=3). GSH and GSSG were also measured in rat plasma. Baseline values of 897+/-210 microM (GSH) and 215+/-61 microM (GSSG) were obtained for rat ASL (n=8), whereas 12.4+/-2.7 microM (GSH) and 14.8+/-6.7 microM (GSSG) were obtained for rat plasma (n=5).
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PMID:Analysis of glutathione in rat airway surface liquid by capillary zone electrophoresis with conductivity detection. 1270 77


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