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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

----------------------------------------------------------------------

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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

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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

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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

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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

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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

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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

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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

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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

----------------------------------------------------------------------

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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

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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

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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

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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

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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 B). 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.

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