Asthma

Asthma and oxidative stress

Asthma is associated with inflammation and oxidative stress.  With a decreased amount of glutathione in the liver and in the lungs; inflammation increases.  While there a number of herbal remedies that effectively deal with asthma; increasing glutathione effectively helps reduce inflammation thereby enabling the lungs more effectively.  The articles below elaborate the connection between glutathione and the lungs.

For further information contact Dr. Holly at holly@choicesunlimited.ca

According to Jimmy Gutman, MD, GACEP, author of GSH, The Body’s Most Powerful Protector states...

 “There is a direct correspondence between low glutathione levels and the severity of the asthma attack.”

He went on to tell how Dr. Carol Trenga presented to the American Lung Association an antioxidant cocktail that helped asthmatics particularly sensitive to air pollutants. Many of the elements of the cocktail were GSH precursors.

 Published ahead of print on December 6, 2007, doi:10.1165/rcmb.2007-0128OC

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American Journal of Respiratory Cell and Molecular Biology. Vol. 38, pp. 509-516, 2008
© 2008 American Thoracic Society
DOI: 10.1165/rcmb.2007-0128OC

Lung Lining Fluid Glutathione Attenuates IL-13–Induced Asthma

Matthew H. Lowry¹, Brian P. McAllister¹, Jyh-Chang Jean¹, Lou Ann S. Brown², Rebecca P. Hughey³, William W. Cruikshank¹, Sal Amar⁴, Edgar C. Lucey¹, Kathleen Braun⁵, Pamela Johnson⁵, Thomas N. Wight⁵ and Martin Joyce-Brady¹

	DISCUSSION

 
Asthma is characterized by inflammation, and oxidants derivedfrom inflammatory cells contribute to the oxidant-antioxidantimbalance and oxidant stress that are associated with asthmapathogenesis (1). Whether attenuation of oxidant stress alonecan affect the phenotype of asthma is unclear (23). Our studies,exposing GGT^enu1 mice to IL-13, were designed to explore theselective role of glutathione metabolism and oxidant stressin an experimental model of asthma (9). Glutathione metabolismis regulated by the ectoenzyme GGT. Loss of GGT enzyme activityimpairs glutathione metabolism, limits cysteine availability,and causes deficiency of intracellular glutathione pools. Thisis particularly evident in endothelial cells, alveolar macrophages,and bronchiolar Clara cells in the GGT^enu1 lung even in normoxia.Upon exposure to hyperoxia, where metabolism of oxygen increasesthe level of intracellular reactive oxygen species and inducesoxidant stress, these cells are injured more rapidly so thatthe onset of pulmonary edema, hemorrhage, and death is acceleratedin GGT^enu1 mice compared with WT mice (8).

We hypothesized that deficiency of cellular glutathione poolswould increase oxidant stress and accentuate the asthma phenotypein the GGT^enu1 mouse lung after IL-13 treatment. However, ourexperiments show that the asthma phenotype is attenuated inthese mice despite IL-13 delivery, cytokine activation, andinflammatory cell and matrix-associated protein accumulationto levels seen in WT mouse lung. The attenuated asthmatic responseoccurred specifically in airway epithelial cells as decreasedlevels of airway mucous cell hyperplasia, mucin protein, andMuc5ac gene induction and EGFR gene induction and receptor activation.

Airway hyperreactivity, one of the hallmarks of asthma, wasprevented in the GGT^enu1 mice, suggesting that hyperreactivityis linked to oxidant-induced airway epithelial cell signalingrather than airway inflammation and cytokine release. Pharmacologicinhibition of GGT activity in lung lining fluid of WT mice alsoattenuated IL-13–induced epithelial cell activation andairway hyperreactivity, demonstrating that lung lining fluidGGT activity, rather than other metabolic consequences of theGGT^enu1 mutation, prevented IL-13–induced asthma.

GGT regulates extracellular glutathione pools in the plasma(6) and the lung lining fluid (8). In the absence of turnover,the plasma glutathione pool enlarges 5-fold (6, 7) and the lunglining fluid pool 2-fold (8) in the GGT-deficient GGT^enu1 mousecompared with WT mice at baseline. This abundance of lung liningfluid glutathione in GGT^enu1 mice increased after IL-13 treatment,and the lack of accumulation of protein carbonyls in BALF confirmsan augmention of antioxidant buffering capacity against thereactive oxidant species generated by inflammatory cells.

Studies in humans suggest that lung lining fluid glutathioneis dynamic in patients with asthma. Total glutathione increasesin BALF (24) and in supernatant from induced sputum (25). Extracellularglutathione protects human airway epithelial cells against toxicityfrom hexamethylene diisocyanate, an in vitro model of isocyanate-inducedasthma (26). There is an inverse correlation between BALF glutathioneand airway hyperreactivity to methacholine (24). Our resultsin the GGT^enu1 mouse lung support these human data.

We considered that the lack of IL-13–induced airway hyperreactivityin the GGT^enu1 mouse lung could involve the accumulation ofglutathione-related molecules such as the nitrosothiol GSNO,an endogenous bronchodilator (27). However, we were unable todetect any difference in GSNO content in BALF between IL-13–treatedGGT^enu1 or WT mice. Enhanced lung lining fluid glutathione contentalone could explain our result in the GGT^enu1 mouse becauseits antioxidant activity affects airway tone (28).

Although GGT may be involved in the production of the bronchoconstrictivecysteinyl leukotriene LTD4, recent mouse data show that LTC4to LTD4 metabolism is mainly regulated by gamma-glutamyl leukotrienase(Ggtla1), a GGT-related enzyme that is encoded by a separategene (22). Loss of Ggtla1 activity, but not GGT activity, increasesairway hyperreactivity as LTC4 accumulates without metabolism.Absence of IL-13–induced airway hyperreactivity in theGGT^enu1 mouse lung is unlikely to be related to altered cysteinylleukotriene metabolism. Our data concur with the hypothesisthat the major function of GGT in the mouse is glutathione metabolism.

Our results support a role for enhanced antioxidant activityin the extracellular glutathione pool as a mechanism for attenuationof IL-13–mediated asthma in the GGT^enu1 mouse lung. Thisextracellular pool does not affect the IL-13–induced inflammatoryresponse, which was similar in WT and GGT^enu1 mice. Rather,we propose that it protects airway epithelial cells by bufferingthe oxidizing milieu created by the inflammatory response inducedby IL-13. These data directly implicate the epithelial cellin the process that leads to airway hyperreactivity becausethe absence of EGFR activation is associated with absence ofairway hyperreactivity.

Previously glutathione aerosols have be used to alter lung liningfluid glutathione in asthma (29), but these had limited successand induced bronchoconstriction (30). Ingestion of the prodrugN-acetylcysteine failed to elevate lung or lung lining fluidglutathione content (31, 32). Pharmacologic inhibition of lunglining fluid glutathione metabolism seems to be a robust strategyto enhance lung lining fluid glutathione content in the presenceof oxidant stress associated with inflammation. A class of -phosphonodiester glutamate analogues is available as novel GGT inhibitorswith greater potency and specificity than acivicin (33). Webelieve that this mechanism should be studied further as a meansof preventing or treating asthma inasmuch as lung lining fluidglutathione has been proposed as an antioxidant shield thatprotects the airway epithelium (4) and EGFR is a signaling systemthat is affected by epithelial barrier integrity (34). Althoughexperiments with allergen challenged GGT^enu1 mice will be importantto extend these results, augmentation of lung lining fluid glutathioneby inhibiting metabolism, combined with supplementation of cellularglutathione pools with -GCS (3), may be a relevant strategyto protect airway epithelium while modulating immune cell functionin asthma and other inflammatory lung diseases, inasmuchas oxidantstress associated with inflammation is emerging as a commonfactor in the pathogenesis of lung injury (35).

	Acknowledgments

 
The authors thank JunLing Yang, Lillian Cross, and Fengzhi Shaofor technical assistance. IL-13 was the generous gift of WyethPharmaceutical, Cambridge, MA, through an MTA with Martin Joyce-Brady.

	Footnotes

 

This work was supported by National Institutes of Health grantsDK054787 (R.P.H.) and HL076801 and DE15989 (S.A.) and ProgramProject PO1 HL47049 (M.J.-B.).

This article has an online supplement, which is accessible fromthis issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1165/rcmb.2007-0128OCon December 6, 2007

Conflict of Interest Statement: None of the authors has a financialrelationship with a commercial entity that  

 

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Medical advice, diagnosing or treating any health condition.

Updated September 1, 2010