Alveolar Fluid Glutathione Decreases in Asymptomatic HIV-Seropositive Subjects Over Time

Pacht, Eric R.; Diaz, Phil; Clanton, Thomas O.; Hart, Judy; Gadek, James E.

doi:10.1378/chest.112.3.785

Cited by 47 publications

(29 citation statements)

References 27 publications

(21 reference statements)

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“…[2][3][4] This increase in COPD is thought to be due to an increased prevalence of smoking in patients with HIV/ AIDS [5][6][7][8][9][10][11][12] in combination with a detrimental amplified inflammatory response in the lungs of those exposed to toxins in cigarette smoke. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Patients with HIV/AIDS also have increased barriers to smoking cessation, which adds to the risk for COPD over time. 30 Prior pulmonary infection with Pneumocystis jiroveci or other pathogens may also influence lung function.…”

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confidence: 99%

Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study

Shirley¹,

Kaner

Glesby

2015

AIDS Patient Care and STDs

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Increased smoking and a detrimental response to tobacco smoke in the lungs of HIV/AIDS patients result in an increased risk for COPD. We aimed to determine the predictive value of a COPD screening strategy validated in the general population and to identify HIV-related factors associated with decreased lung function. Subjects at least 35 years of age at an HIV clinic in New York City completed a COPD screening questionnaire and peak flow measurement. Those with abnormal results and a random one-third of normal screens had spirometry. 235 individuals were included and 89 completed spirometry. Eleven (12%) had undiagnosed airway obstruction and 5 had COPD. A combination of a positive questionnaire and abnormal peak flow yielded a sensitivity of 20% (specificity 93%) for detection of COPD. Peak flow alone had a sensitivity of 80% (specificity 80%). Abnormal peak flow was associated with an AIDS diagnosis ( p = 0.04), lower nadir ( p = 0.001), and current CD4 counts ( p = 0.001). Nadir CD4 remained associated in multivariate analysis (p = 0.05). Decreased FEV1 ( < 80% predicted) was associated with lower CD4 count nadir ( p = 0.04) and detectable current HIV viral load ( p = 0.01) in multivariate analysis. Questionnaire and peak flow together had low sensitivity, but abnormal peak flow shows potential as a screening tool for COPD in HIV/AIDS. These data suggest that lung function may be influenced by HIV-related factors.

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confidence: 99%

Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study

Shirley¹,

Kaner

Glesby

2015

AIDS Patient Care and STDs

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“…mented (3)(4)(5)(6)(7)(8). For the purpose of detoxification and to respond to extracellular oxidative stress, cells express membrane proteins capable of transporting GSH, glutathione disulfide (GSSG), and GSH conjugates (GS-X).…”

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confidence: 99%

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

Brechbuhl

Gould

Kachadourian

et al. 2010

Journal of Biological Chemistry

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Glutathione (GSH) transport is vital for maintenance of intracellular and extracellular redox balance. Only a few human proteins have been identified as transporters of GSH, glutathione disulfide (GSSG) and/or GSH conjugates (GS-X). Human epithelial MDA1586, A549, H1975, H460, HN4, and H157 cell lines were exposed to 2,5-dihydroxychalcone, which induces a GSH efflux response. A real-time gene superarray for 84 proteins found in families that have a known role in GSH, GSSG, and/or GS-X transport was employed to help identify potential GSH transporters. ABCG2 was identified as the only gene in the array that closely corresponded with the magnitude of 2,5-dihydroxychalcone (2,5-DHC)-induced GSH efflux. The role of human ABCG2 as a novel GSH transporter was verified in a Saccharomyces cerevisiae galactose-inducible gene expression system. Yeast expressing human ABCG2 had 2.5-fold more extracellular GSH compared with those not expressing ABCG2. GSH efflux in ABCG2-expressing yeast was abolished by the ABCG2 substrate methotrexate (10 M), indicating competitive inhibition. In contrast, 2,5-DHC treatment of ABCG2-expressing yeast increased extracellular GSH levels in a dose-dependent manner with a maximum 3.5-fold increase in GSH after 24 h. In addition, suppression of ABCG2 with short hairpin RNA or ABCG2 overexpression in human epithelial cells decreased or increased extracellular GSH levels, respectively. Our data indicate that ABCG2 is a novel GSH transporter.Glutathione (GSH) is a tripeptide (␥-glutamyl-cysteinyl-glycine) that is maintained at millimolar concentrations within the cell. It is important in many signaling processes, including cell proliferation, post-translational modification of proteins, immune responses, and apoptosis (1, 2). The importance of GSH in normal cell function as well as its role in disease states such as cancer, cystic fibrosis, Parkinson disease, AIDS, liver dysfunction, and a host of other maladies has been well documented (3-8). For the purpose of detoxification and to respond to extracellular oxidative stress, cells express membrane proteins capable of transporting GSH, glutathione disulfide (GSSG), and GSH conjugates (GS-X).2 Currently, there are only a handful of proteins identified as capable of transporting GSH across membranes.The first human protein identified as a GS-X and/or GSSG transporter was the ATP-binding cassette (ABC) protein ABCC1, first called the GSH S-conjugate pump and later identified as the multidrug resistance protein MRP1 (9 -11). Since the discovery of ABCC1 as a GSH transporter, five other ABC family members have been shown to transport GSH and/or GS-X, including ABCC2, ABCC3, ABCC4, ABCC5, and ABCC7 (12-17). GSH transport has also been linked to the organic anion transporting polypeptide protein family, a subfamily of the solute carrying (SLC) protein superfamily. The SLC superfamily also contains mitochondria-specific membrane proteins (SLC25) capable of transporting GSH (18).Numerous compounds stimulate GSH, GSSG, and GS-X efflux through the ABC protei...

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“…In many of these cases, the elevated GSH levels are thought to be a lung-adaptive response to oxidants. On the other hand, basal GSH levels in ELF are low in individuals who are acute smokers (42), in human immunodeficiency virus-positive subjects (36), and in a number of progressive lung disorders including idiopathic pulmonary fibrosis (IPF) (10), acute respiratory distress syndrome (ARDS) (5,37), and cystic fibrosis (CF) (45). Decreased levels of ELF GSH may make the lung more susceptible to exogenous agents and contribute to chronic oxidative stress.…”

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confidence: 99%

A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

Kariya¹,

Leitner²,

Min³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only known apical glutathione (GSH) transporter in the lung. The purpose of these studies was to determine whether oral GSH or glutathione disulfide (GSSG) treatment could increase lung epithelial lining fluid (ELF) GSH levels and whether CFTR plays a role in this process. The pharmacokinetic profile of an oral bolus dose of GSH (300 mg/kg) was determined in mice. Plasma, ELF, bronchoalveolar lavage (BAL) cells, and lung tissue were analyzed for GSH content. There was a rapid elevation in the GSH levels that peaked at 30 min in the plasma and 60 min in the lung, ELF, and BAL cells after oral GSH dosing. Oral GSH treatment produced a selective increase in the reduced and active form of GSH in all lung compartments examined. Oral GSSG treatment (300 mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR in this process, Cftr knockout (KO) mice and gut-corrected Cftr KO-transgenic (Tg) mice were given an oral bolus dose of GSH (300 mg/kg) and compared with wild-type mice for changes in GSH levels in plasma, lung, ELF, and BAL cells. There was a twofold increase in plasma, a twofold increase in lung, a fivefold increase in ELF, and a threefold increase in BAL cell GSH levels at 60 min in wild-type mice; however, GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and twofold in the BAL cells within the gut-corrected Cftr KO-Tg mice. No change in GSH levels was observed in the uncorrected Cftr KO mice. These studies suggest that CFTR plays an important role in GSH uptake from the diet and transport processes in the lung.

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Alveolar Fluid Glutathione Decreases in Asymptomatic HIV-Seropositive Subjects Over Time

Cited by 47 publications

References 27 publications

Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study

Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study

Glutathione Transport Is a Unique Function of the ATP-binding Cassette Protein ABCG2

A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

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