Guest guest Posted August 9, 2003 Report Share Posted August 9, 2003 Here is a little night reading, very informative, copied from Sharktank Enjoy, mom of a 10 wcf, Venanzio 7 nocf, Pepe 3 nocf Authors Roum JH. Borok Z. McElvaney NG. Grimes GJ. Bokser AD. Buhl R. Crystal RG. Title Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis Source Journal of Applied Physiology. 87(1):438-443, 1999 Jul. Abstract 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 (O-2(-).) 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 O-2(-). 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. [References: 45] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Reznick AZ. Han D. Packer L. Title CIGARETTE SMOKE INDUCED OXIDATION OF HUMAN PLASMA PROTEINS, LIPIDS, AND ANTIOXIDANTS - SELECTIVE PROTECTION BY THE BIOTHIOLS DIHYDROLIPOIC ACID AND GLUTATHIONE Source Redox Report. 3(3):169-174, 1997 Jun. Abstract Exposure of human plasma to gas-phase cigarette smoke (CS) causes loss of human plasma antioxidants, protein modification (Frei et al, Biochem J. 1991 277: 133-138; Reznick et al, Biochem J. 1992 286: 607-611) and a minimal amount of lipid oxidation. Ascorbic acid was found to prevent CS-induced lipid peroxidation and glutathione (GSH) partially protected against protein modification, as determined by loss of protein -SH groups and by increases in carbonyl content as a measure of protein oxidation. In the present study we demonstrate that dihydrolipoic acid (0.25-1.0 mM) decreases CS-induced protein carbonyls, alpha-tocopherol loss, and lipid hydroperoxide formation in plasma. In contrast GSH (1 mM) failed to influence CS-induced loss of alpha-tocopherol, and was 50% as effective as dihydrolipoate in protecting against CS-induced protein carbonyl formation. On the other hand, lipoic acid (oxidized form of dihydrolipoic acid) and oxidized glutathione (GSSG) had minimal effect in protecting against the CS-induced protein modifications. These findings demonstrate that low molecular weight thiols are capable of modifying the effect of gas-phase CS on biological fluids. Dihydrolipoate appears to be particularly useful in that it was shown to conserve ascorbic acid and a-tocopherol, i.e. supporting the antioxidant network concept in protection against protein and lipid oxidation. [References: 35] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Marrades RM. Roca J. Barbera JA. Dejover L. Macnee W. roisin R. Title NEBULIZED GLUTATHIONE INDUCES BRONCHOCONSTRICTION IN PATIENTS WITH MILD ASTHMA Source American Journal of Respiratory & Critical Care Medicine. 156 (2):425-430, 1997 Aug. Abstract To assess the effects on bronchial responsiveness of nebulized glutathione (GSH), one of the most efficient scavengers of oxidant substances in the airways, we studied eight patients with mild asthma (FEV1, 88 +/- 11% predicted [sD]) in a randomized, double-blind, cross-over, placebo-controlled fashion. Bronchial challenge was measured using both FEV1 and total pulmonary resistance (Rrs) by the forced oscillation technique. Patients received nebulized GSH (600 mg with 4 ml of 0.9% sodium chloride) or placebo (identical saline solution) over a period of 25 min, 1 wk apart. Placebo provoked subclinical mild bronchoconstriction (changes from baseline: FEV1, -1%; Rrs, +17%); by contrast, GSH caused major airway narrowing (changes from baseline: FEV1, -19%; Rrs, +61%) and induced cough (four patients) or breathlessness (three patients). Differences between placebo and GSH after challenge were also noticeable in both FEV1 (p = 0.03) and Rrs (p = 0.02). Neither osmolarity (660 mosm . kg(-1)) nor pH (3.0) of the GSH solution accounted for these effects. Nebulized salbutamol (5.0 mg) given before the GSH challenge blocked GSH-induced bronchoconstriction. Furthermore, GSH-induced FEV1 falls were inversely correlated with metabisulfite bronchoprovocation (provocative dose [PD20], 1.49 +/- 1.83 mu mol) but not with methacholine challenge. The detrimental effects of nebulized GSH on the airway bronchial tone in patients with mild asthma strongly suggests bronchoconstriction provoked by sulfite formation. [References: 29] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Gillissen A. Jaworska M. Orth M. Coffiner M. Maes P. App EM. Cantin AM. Schultzewerninghaus G. Title NACYSTELYN, A NOVEL LYSINE SALT OF N-ACETYLCYSTEINE, TO AUGMENT CELLULAR ANTIOXIDANT DEFENCE IN VITRO Sourc Respiratory Medicine. 91(3):159-168, 1997 Mar. Abstract Nacystelyn (NAL), a recently-developed lysine salt of N- acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O-2(-) and H2O2 in cell-free assay systems; (2) to reduce O-2(-) and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O-2(-), in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l(-1)) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l(-1)), total intracellular GSH (GSH-t2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAG), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAG, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n=10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l(-1)). In accordance with the results obtained from cell-free, in vitro assays, O-2(-) released by PMN was not affected. Ambroxol (concentrations: 10(-9)-10(-3) mol l(-1)) did not reduce activity levels of H2O2 and O-2(-) in vitro. Due to the basic effect of dissolved lysine, which separates easily in solution from NAL, the acidic function of the remaining NAC molecule is almost completely neutralized [at concentration 2 x 10(-4) M: pH 3.6 (NAC), PH 6.4 (NAL)]. Due to their function as H2O2 scavengers, and due to their ability to enhance cellular glutathione levels, NAL and NAC both have potent antioxidant capabilities in vitro. The advantage of NAL over NAC is two-fold; it enhances intracellular GSH levels twice as effectively, and it forms neutral pH solutions whereas NAC is acidic. Concluding from these in vitro results, NAL could be an interesting alternative to enhance the antioxidant capacity at the epithelial surface of the lung by aerosol administration. [References: 48] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Gillissen A. Scharling B. Jaworska M. Bartling A. Rasche K. Schultzewerninghaus G. Title OXIDANT SCAVENGER FUNCTION OF AMBROXOL IN VITRO - A COMPARISON WITH N-ACETYLCYSTEINE Source Research in Experimental Medicine. 196(6):389-398, 1997 Mar. Abstract Highly reactive oxygen metabolites play an important role in inflammatory processes in the lung. Ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl] benzylamine) has been shown to reduce oxidant-mediated cell damage. However, the mechanism of this effect remains unclear. In order to evaluate oxidant scavenger function increasing concentrations of ambroxol (0-10(-3) mol/l) were compared with equimolar concentrations of N-acetylcysteine (NAG) and glutathione (GSH) in vitro to reduce OH. (hydroxyl radical), HOCl (hypochlorous acid), O-2 (-) (superoxide anion) and H2O2 (hydrogen peroxide). OH. was measured spectrophotometrically (deoxyribose assay); O-2(-) (xanthine/x- oxidase), H2O2 and HOCl (HOCI/OCl-) were determined by chemiluminescence. Ambroxol, NAC and reduced GSH scavenged OH. significantly at 10(-3) mol/l, while HOCl was inhibited at concentrations greater than or equal to 10(-4) mol/l completely (P<0.01). NAC and GSH had no anti-O-2(-) function, while ambroxol (10(-4) mol/l) reduced O-2(-) by 14.3+/-6.7%. In contrast, GSH and NAC scavenged H2O2 at >10(-6) mol/l (P<0.01), while ambroxol had no anti- H2O2 effect. Our data demonstrate direct oxidant-reducing capabilities of ambroxol, which may be directly related to the aromatic moiety of the molecule. However, high concentrations (micromolar concentrations) are needed. Due to differences in direct oxidant scavenger function, a combination of ambroxol and NAC could be beneficial in antioxidant therapy. [References: 38] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Gillissen A. Wickenburg D. Vanzwoll D. Schultzewerninghaus G. Title BETA-2-AGONISTS HAVE ANTIOXIDANT FUNCTION IN VITRO .2. THE EFFECT OF BETA-2-AGONISTS ON OXIDANT-MEDIATED CYTOTOXICITY AND ON SUPEROXIDE ANION GENERATED BY HUMAN POLYMORPHONUCLEAR LEUKOCYTES Source Respiration. 64(1):23-28, 1997 Jan-Feb. Abstract Therapeutic agents which may be able to enhance the antioxidant screen of the epithelial surface of the lung have the potential to influence the progression of lung inflammation. This study evaluates the efficacy of a variety of antiasthma drugs to reduce oxidant-mediated cytotoxicity and to inhibit superoxide anion generated by human polymorphonuclear leukocytes. We quantified in vitro the prevention of H2O2-mediated cytotoxicity (lactate dehydrogenase release assay) using the antiasthma drugs as follows: ipratropium bromide, salbulamol (salbutamol base), fenoterol (fenoterol hydrobromide), terbutaline (terbutaline sulfate), isoproterenol, prednisolone (prednisolone hydrogensuccinate), beclomethasone (17,21-beclomethasone dipropionate) and reduced glutathione. Furthermore, fenoterol and isoproterenol were evaluated ex vivo to reduce superoxide anion (O-2(-)) generated by freshly isolated polymorphonuclear cells (PMN) from smokers with chronic obstructive lung disease (n = 10). Using a concentration of 10(-4)M reduction of cytotoxicity was quite different among beta(2)-agonists: fenoterol (97.8%) > isoproterenol (67.6%) > salbulamol (41.8%) > terbutaline (30.5%) > ipratropium bromide (18.1%). Corticosteroids and theophylline had no antioxidant effect. The cellular O-2(-) production of freshly isolated PMN was significantly (p < 0.05, comparisons O vs. greater than or equal to 10(-7) M) reduced with fenoterol and isoproterenol at concentrations greater than or equal to 10(-7) M. Propranolol had no inhibitory effect on antioxidant properties of beta(2)-agonists. We hypothesize that the antioxidant function of beta(2)-agonists is related to the number and formation of hydroxyl groups of the phenol rings within their molecular structure. These results demonstrate that beta(2)-agonists have in part a good intrinsic scavenger function on reactive oxygen species when used in micromolar concentrations. However. to achieve this effect supratherapeutic concentrations were necessary. Thus, the conceivable benefit of beta(2)-agonists in the treatment of high oxidant burden in vivo seems doubtful. [References: 39] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Vogelmeier C. Gillissen A. Buhl R. Title USE OF SECRETORY LEUKOPROTEASE INHIBITOR TO AUGMENT LUNG ANTINEUTROPHIL ELASTASE ACTIVITY Source Chest. 110(6 Suppl S):S 261-S 266, 1996 Dec. Abstract Physiologically, secretory leukoprotease inhibitor (SLPI) is the major antiprotease of the epithelium of the upper respiratory tract providing protection against neutrophil elastase (NE). The recombinant form of SLPI (rSLPI) has several advantages compared with alpha(1)-antitrypsin that make it interesting as potential therapy. In vitro, rSLPI proves to be an excellent inhibitor of NE. When administered as an aerosol in vitro and in vivo, the structure and function of rSLPI remain intact. Using the aerosol route, the half-life of rSLPI in respiratory epithelial lining fluid is 12 h; thus, giving it twice daily should guarantee satisfactory levels in the lung. Following inhalation, rSLPI moves from the epithelium in an intact form into the interstitium of the lung. Following on from these in vitro and in vivo experiments, a short-term study in patients with cystic fibrosis was performed,vith aerosolized rSLPI. Promising results relative to NE level reduction and the consequences for the inflammatory process in the bronchi were achieved. rSLPI not only induced an increase of the anti-NE protective screen, but also improved the antioxidant protection by raising glutathione levels in the lung in sheep. rSLPI may therefore provide a unique opportunity for protecting the lung from the damage caused by inflammatory processes by giving a single drug. [References: 58] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Buhl R. Meyer A. Vogelmeier C. Title OXIDANT-PROTEASE INTERACTION IN THE LUNG - PROSPECTS FOR ANTIOXIDANT THERAPY Source Chest. 110(6 Suppl S):S 267-S 272, 1996 Dec. Abstract In inflammatory lung disorders, oxidants and proteases complement each other in their potential to destroy lung parenchyma. It is therefore rational to combine therapeutic strategies aimed at augmenting the antiproteolytic defenses of the lung in diseases such as emphysema with antioxidant strategies. In the healthy lung, the oxidant burden is balanced by the local antioxidant defenses. However, both an increased oxidant burden and/or decreased antioxidant defenses may reverse the physiologic oxidant-antioxidant balance in favor of oxidants, leading to lung injury. This concept points to an obvious therapeutic strategy: augmentation of the antioxidant screen of the lung to prevent oxidant-mediated tissue damage. Studies using reduced glutathione (GSH), the major pulmonary antioxidant, as a model therapeutic agent demonstrated that GSH can be administered directly to the respiratory epithelial surface by aerosol and is fully functional as an antioxidant both in vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary fibrosis or following HN infection, GSH aerosol therapy not only normalized deficient pretherapy GSH levels in the lung, but was capable of favorably influencing cellular events such as oxidant release by pulmonary inflammatory cells, The same was true for oral antioxidant therapy with N-acetylcysteine, a glutathione precursor. These results suggest that it is possible to use antioxidants to reverse the imbalance between oxidants and antioxidants at the site of oxidant injury to prevent the progressive tissue damage in lung disorders characterized by high oxidant states, Antioxidants, alone and in combination with antiproteases, merit further long-term studies for clinical therapy. [References: 57] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Bernorio S. Pecis M. Zucchi A. Guerra G. Migliorini V. Negri L. Corsano A. Title GLUTATHIONE IN BRONCHIAL HYPERRESPONSIVENESS Source Journal of Aerosol Medicine-Deposition Clearance & Effects in the Lung. 9(2):207-213, 1996 Sum. Abstract Alterations of oxidants and antioxidants now appear to be pivotal in the development of bronchial hyperresponsiveness and bronchial asthma, To evaluate the potential protective role of the antioxidant reduced glutathione (GSH) administered by ultrasonic nebulizer on metacholine-induced bronchoconstriction, we designed a double- blind, randomized study enrolling 18 subjects,vith mild asthma and previous bronchoconstriction after a methacholine challenge; we did not find a statistically significant decrease in bronchoconstriction after premedication with inhaled GSH, Further investigation under different experimental conditions is warranted because our information about the mode of action and pharmacokinetics of GSH is still incomplete and sometimes the data are conflicting. [References: 19] Publication Type Article http://www.thorne.com/n_acetylcysteine.html : Significance of glutathione in lung disease and implications for therapy. Glutathione is a tripeptide that contains an important thiol (sulfhydryl) group within the central cysteine amino acid. Glutathione is involved in numerous vital processes where the reducing potential of the thiol is used. Several lung disorders are believed to be characterized by an increase in alveolar oxidant burden, potentially depleting alveolar and lung glutathione. Low glutathione has been linked to abnormalities in the lung surfactant system and the interaction between glutathione and antiproteases in the epithelial lining fluid of patients. Normal levels of intracellular glutathione may exert a critical negative control on the elaboration of proinflammatory cytokines. The increase of intracellular reactive oxygen species is believed to correlate with the activation of NF-kappa B, a strongly implicate free radical injury in the genesis and maintenance of several lung disorders in humans. This information is substantial and will help the development of clinical studies examining a variety of inflammatory lung disorders. PE;Bernard GR. Significance of glutathione in lung disease and implications for therapy. Am J Med Sci 307:119-127;1994 ---------------------------------------------------------------------- ---------- Authors Lands LC. Grey V. Smountas AA. Kramer VG. McKenna D. Title Lymphocyte glutathione levels in children with cystic fibrosis Source Chest. 116(1):201-205, 1999 Jul. Abstract Objective: Lung disease in cystic fibrosis (CF) is characterized by a neutrophilic inflammatory response. This can lead to the production of oxidants, and to oxidative stress in the lungs. Glutathione (GSH) represents the primary intracellular antioxidant, and provides an important defense in the epithelial lining fluid. Evidence suggests that lymphocyte GSH reflects lung GSH concentrations, and so could potentially serve as a peripheral marker of lung inflammation. Methods: We assessed peripheral blood lymphocyte GSH concentrations in 20 children (13 boys) with CF who were in stable condition at the time of evaluation. Values were compared with nutritional status and lung function parameters. Results: Patients were 11.7 +/- 3.03 years old (mean +/- SD). Their percentage of ideal body weight was 101.8 +/- 17.92%; FEV1, 79.5 +/- 19.22% predicted; FEV1/FVC, 75.0 +/- 10.08%; and residual volume (RV)/total lung capacity (TLC), 31.3 +/- 10.47%. For the group, the GSH concentration was 1.31 +/- 0.52 mu mo/10(6) lymphocytes, which was not different from laboratory control values. GSH values were correlated with nutritional status (percentage of ideal body weight: r = 0.49, p < 0.03) and the degree of gas trapping (RV/TLC: r = 0.50, p < 0.03), and were correlated inversely with airflow limitation (FEV1, percent predicted: r = -0.45, p < 0.05; FEV1/FVC: r = -0.48 is, p < 0.04), but not with age, height, or weight (p > 0.1). Conclusions: We interpret the inverse correlation between lymphocyte GSH concentration and lung function as a reflection of upregulation of GSH production by lung epithelial tissue in response to oxidative stress. We interpret the correlation between lymphocyte GSH concentration and nutritional status as a reflection of the role of cysteine in hepatic glutamine metabolism. Peripheral blood lymphocyte GSH concentration may potentially serve as a convenient marker of lung inflammation. Furthermore, the increased demand for GSH production in the face of ongoing inflammation suggests a potential role for supplementation with cysteine donors. [References: 39] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Roum JH. Borok Z. McElvaney NG. Grimes GJ. Bokser AD. Buhl R. Crystal RG. Title Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis Source Journal of Applied Physiology. 87(1):438-443, 1999 Jul. Abstract 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 (O-2(-).) 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 O-2(-). 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. [References: 45] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Gao L. Kim KJ. Yankaskas JR. Forman HJ. Title Abnormal glutathione transport in cystic fibrosis airway epithelia Source American Journal of Physiology - Lung Cellular & Molecular Physiology. 21(1):L113-L118, 1999 Jul. Abstract 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), Delta F508 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. [References: 28] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Linsdell P. Hanrahan JW. Title GLUTATHIONE PERMEABILITY OF CFTR Source American Journal of Physiology - Cell Physiology. 44(1):C 323- C 326, 1998 Jul. Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) forms an ion channel that is permeable both to Cl- and to larger organic anions. Here we show, using macroscopic current recording from excised membrane patches, that the anionic antioxidant tripeptide glutathione is permeant in the CFTR channel. This permeability may account for the high concentrations of glutathione that have been measured in the surface fluid that coats airway epithelial cells. Furthermore, loss of this pathway for glutathione transport may contribute to the reduced levels of glutathione observed in airway surface fluid of cystic fibrosis patients, which has been suggested to contribute to the oxidative stress observed in the lung in cystic fibrosis. We suggest that release of glutathione into airway surface fluid may be a novel function of CFTR. [References: 21] Publication Type Article ---------------------------------------------------------------------- ---------- Authors Grimble RF. Title MODIFICATION OF INFLAMMATORY ASPECTS OF IMMUNE FUNCTION BY NUTRIENTS Source Nutrition Research. 18(7):1297-1317, 1998 Jul. Abstract The pro-inflammatory cytokines interleukin 1 (IL1) interleukin 6 (IL6) and tumour necrosis factor-alpha (TNF), and reactive oxygen species (ROS), play a-major role in inflammatory aspects of immune function. They are closely linked with pathology in a wide range of diseases and condition which have an inflammatory basis. Alterations in the intake of fats, antioxidant nutrients, protein and specific amino acids change many aspects of inflammation by interacting with cytokine and ROS biology, thereby providing a means of modulating inflammation. Mortality and morbidity, in a diverse range of diseases, have been linked with excessive or untimely oxidant and pro-inflammatory cytokine production. Evidence of oxidative damage has been observed in sepsis, HIV and hepatitis infection, cancer, diabetes mellitus, alcoholic liver disease and cystic fibrosis. ROS produced during the inflammatory response enhances pro-inflammatory cytokine production by activation of nuclear factor kappa B (NF kappa . The interaction is an important part of the up-regulation of inflammatory aspects of immune function. The interaction between ROS and cytokines has the potential to damage the host but is held in check by the antioxidant defences. Nutrient intake directly and indirectly influences antioxidant defence. Glutathione is a major endogenous antioxidant and is important for lymphocyte replication. Vitamin B, and riboflavin participate in the maintenance of glutathione status. Vitamin B, acts as a cofactor in the synthesis of cysteine (the rate limiting precursor for glutathione biosynthesis) and riboflavin is a cofactor for glutathione reductase. Deficiencies in vitamins E, B, and riboflavin reduce cell numbers in lymphoid tissues of experimental animals and produce functional abnormalities in the cell mediated immune response. Sulphur amino acid deficient rats exhibit an impaired ability to synthesise glutathione during inflammation and have increased numbers of neutrophils in lung. Ascorbic acid and tocopherols exert anti- inflammatory effects in studies in man and animals. In humans, dietary supplementation with ascorbic-acid, tocopherols and vitamin B, enhances a number of aspects of lymphocyte function-In smokers indices of inflammation inversely relate to the intakes of vitamins C and E. Studies in healthy subjects, patients and experimental animals clearly demonstrate that unsaturated fats modulate pro-inflammatory cytokine biology. In general n-6 polyunsaturated fatty acids enhance, and n-3 PUFAs and monounsaturated fatty acids suppress, cytokine mediated aspects of inflammation. In addition, n-6 PUFAs and cholesterol enhance and n-3 PUFAs suppress cytokine production. Fats rich in n-3 PUFAs are efficacious in a number of inflammatory diseases, however in smokers indices of inflammation are enhanced in subjects consuming greater than 5% of dietary energy in the form of n-6 PUFAs. Fats may modulate cytokine biology by a number of mechanisms closely linked to membrane phospholipid composition. As a consequence of diet induced change, alterations in prostaglandin, leukotriene and diacyl glycerol production, protein kinase C activation and fluidity may occur. Recent studies suggest that changes in bulk membrane fluidity are unlikely to underlie the substantial modulatory effects of fats on cytokine biology. In conclusion nutrients have a major potential for modulating inflammatory aspects of immune function due to interaction with three main areas whereby inflammation is prosecuted and controlled. Firstly by changing provision of substrate for the synthesis of molecules for components for the executive and control systems (protein, sulphur amino acids, glutamine). Secondly by modulating the composition of the membranes of cells involved in the inflammatory process (unsaturated fatty acids and cholesterol) and thirdly by influencing the interaction between ROS and NF kappa B activation (sulphur amino acids, vitamins C and E, and riboflavin). © 1998 Elsevier Science Inc. [References: 130] Publication Type Review Funded Pilot Projects - Abstracts Year 6: April 1, 2000-March 31, 2001 Role of Glutamate-L-cysteine Ligase in Cystic Fibrosis Terrance J. Kavanagh, PhD, Associate Professor, Department of Environmental Health, UW Cystic fibrosis is a debilitating systemic disorder that affects the lungs, the pancreas and the intestine. Most CF is thought to be due to a mutation in the cystic fibrosis transmembrane regulator protein (CFTR0. However, other factors certainly contribute the severity and progression of this disease. Recently, it has been shown that CFTR may influence the ability of airway epithelial cells to transport the antioxidant glutathione. Glutathione is important in preserving lung function in the face of oxidative stress, which is a frequent occurrence in CF. Individuals with CF have been shown to have lower levels of GSH in their alveolar lining fluid. This suggests that CF may be characterized by an inability to supply the alveolus with sufficient GSH. We have recently shown that a polymorphism in the GSH biosynthetic enzyme glutamate-L-cysteine ligase (GLCL) is associated with risk for idiopathic pulmonary fibrosis, a condition that also is characterized by low GSH in the alveolar lining fluid. The aims of this proposal are to examine the prevalence of the GLCL polymorphism in CF patients, and to assess the association of various alleles with disease severity. This information will help to define the variability in disease severity seen in this condition and also lead to rational antioxidant therapy for these patients. This website contains cystic fibrosis research. This research explores how to correct the condition of cystic fibrosis. The remedies for cystic fibrosis mentioned on this site are hypothetical and untested. SharkTank Research International does not suggest, recommend, imply or, in any way, advise you to undertake any remedy mentioned on this website without your medical professional's supervision and consent. Quote Link to comment Share on other sites More sharing options...
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