Environmental toxicity, redox signaling and lung inflammation: the role of glutathione - PubMed (original) (raw)

Review

Environmental toxicity, redox signaling and lung inflammation: the role of glutathione

Saibal K Biswas et al. Mol Aspects Med. 2009 Feb-Apr.

Abstract

Glutathione (gamma-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox-sensitive transcription factors such as Nrf2, NF-kappaB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation of GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-l-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Oxidative alteration in the intracellular redox ratio of GSH/GSH levels and redox regulation of pro-inflammatory and anti-inflammatory diseases. Oxidative alteration in the intracellular redox ratio of GSH/GSSG levels by environmental oxidants can modulate NF-κB and AP-1 activation leading to transcription of pro-inflammatory genes. The expression of pro-inflammatory mediators would lead to chronic inflammation which is involved in the pathogenesis of various pulmonary diseases, such as COPD, IPF, ARDS, and asthma. On the other hand during oxidative stress the ARE present in the human GCLC and GCLM promoters is trans-activated by Nrf2 due to alteration in GSH and GSSG ratio leading to synthesis of GSH. The imbalance of antioxidant and pro-inflammatory genes can lead to chronic inflammation. Various thiol compounds, such as N-acetyl-L-cysteine (NAC), N-acystelyn (NAL), N-isobutyrylcysteine (NIC) and erdosteine can supply cysteine for GSH biosynthesis.

Fig. 2

Fig. 2

Chemical structures of key thiol compounds in clinical trials.

Similar articles

Cited by

References

    1. Antonicelli F, Parmentier M, Drost EM, Hirani N, Rahman I, Donaldson K, MacNee W. Nacystelyn inhibits hydrogen peroxide mediated interleukin-8 expression in human alveolar epithelial cells. Free Rad Biol Med. 2002;32:492–502. - PubMed
    1. Aoki T, Suzuki Y, Suzuki K, Miyata A, Oyamada Y, Takasugi T, Mori M, Fujita H, Yamaguchi K. Modulation of ICAM-1 expression by extra-cellular glutathione in hyperoxia-exposed human pulmonary artery endothelial cells. Am J Respir Cell Mol Biol. 1996;15:319–327. - PubMed
    1. Arfsten DP, Johnson EW, Wilfong ER, Jung AE, Bobb AJ. Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage. Cutan Ocul Toxicol. 2007;26:113–134. - PubMed
    1. Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6:593–597. - PubMed
    1. Asti C, Melillo G, Caselli GF, Daffonchio L, Hernandez A, Clavenna G, Omini C. Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness, Pharmacol. Res. 1995;31:387–392. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources