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Smoking, Oxidative/Carbonyl Stress, and Regulation of Redox Signaling in Lung Inflammation

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Systems Biology of Free Radicals and Antioxidants

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Abstract

Lung airspace and epithelium are the primary targets of inhaled environmental insults including oxidants and noxious pollutant gases. Cigarette/tobacco smoke–derived reactive oxygen species (ROS) cause alterations in cellular redox status (GSH/GSSG ratio), thereby activating kinase signaling pathways, redox-sensitive transcription factors (NF-κB and AP-1), and chromatin modification enzymes, resulting in increased pro-inflammatory responses. This phenomenon is due to activation of IκB kinase (IKK) and/or recruitment of coactivator CBP/p300-NF-κB-complex on specific gene promoters, leading to chromatin modifications (histone acetylation or via decreased deacetylation), culminating in pro-inflammatory gene transcription. CS/oxidants alter the levels and activities of HDACs (HDAC2) and sirtuins (SIRT1) by posttranslational modifications (carbonylation/oxidation, nitrosylation, or aldehyde adducts formation), and induce gene expression of pro-inflammatory mediators by chromatin modifications on promoters. CS/oxidant/carbonyl stress decreases glucocorticoid sensitivity by reducing HDAC2 levels/activity which occurs in patients with chronic obstructive pulmonary disease (COPD) and severe asthmatics, where glucocorticoid resistance is shown. Epigenetic dysregulations occur during the development and progression of chronic inflammatory lung diseases due to abnormal expression/activities of epigenetic modification enzymes that regulate chromatin modifications. Epigenetic chromatin modifications are altered in the airway epithelial cells and macrophages obtained from patients with COPD. This chapter provides timely insights and updates on the mechanisms of ROS, carbonyls, and redox signaling on epigenetic regulation by stress kinases, redox-sensitive transcription factors, CBP-HDAC2-NF-κB and SIRT1-FOXO3 pathways, histone acetylation/deacetylation, and the release and expression of pro- and anti-inflammatory mediators, culminating in lung inflammatory response. Ultimately, understanding the redox regulation of CS-mediated intracellular signaling pathways will lead to the development of novel therapies against chronic inflammatory lung diseases including COPD and disease associated with cigarette/tobacco smoking. This will lead to a system-based personalized therapy based on specific targets involved in inflammation.

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Abbreviations

OH•− :

Hydroxyl radical

4-HNE:

4-hydroxy-2-nonenal

AGEs:

Advanced glycation end-products

ALEs:

Advanced lipid peroxidation products

AP-1:

Activator protein-1

ARE:

Antioxidant response element

CBP:

CREB-binding protein

COPD:

Chronic obstructive pulmonary disease

CREB:

cAMP-response-element-binding protein

CS:

Cigarette smoke

ECSOD:

Extracellular superoxide dismutase

ERK:

Extracellular signal-related kinase

FOXO:

Forkhead box O

GCLM:

Glutamate cysteine ligase modifier

GPx:

Glutathione peroxidase

GR:

Glucocorticoid receptor

GSH:

Glutathione

H2O2 :

Hydrogen peroxide

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HO-1:

Heme oxygenase-1

IKK:

IkappaB kinase

IL-8:

Interleukin-8

JNK:

c-Jun N-terminal protein kinase

Keap1:

Kelch-like ECH-associated protein 1

LPS:

Lipopolysaccharide

MDA:

Malondialdehyde

MMP-9:

Matrix metalloproteinase-9

MnSOD:

Manganese SOD

MSK1:

Mitogen- and stress-activated kinase 1

NF-κB:

Nuclear factor κB

NIK:

NF-κB inducing kinase

NO:

Nitric oxide

NQO1:

NAD(P)H quinine oxidoreductase 1

Nrf2:

Nuclear factor erythroid 2 p45-related factor 2

O2 •– :

Superoxide anion

ONOO− :

Peroxynitrite anion

PCAF:

p300-CBP associated factor

PGC-1α:

Peroxisome-proliferator-activated receptor (PPAR) gamma coactivator-1 alpha

PI3K:

Phosphoinositide 3-kinase

PKC:

Protein kinase C

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SIRT1:

Sirtuin1

SOD:

Superoxide dismutase

TNFα:

Tumor necrosis factor-alpha

TSA:

Trichostatin A

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Acknowledgments and Disclosures

We have paid close attention to cite the relevant reviews and papers, but the authors apologize for any oversight in citing the additional references. This is purely due to constraint of space and limit of citations. The authors have also updated various sections based on current literature published either from the same authors or others (PubMed) with citations, and have interpreted the findings based on their scientific knowledge, any oversight is regretted. The scientific/medical terminologies and scientific paradigm remained the same as per public record. Hence, the authors are not responsible for any misconstrued perceptions/thoughts which may arise after the publication of this book chapter which is solely a review of literature. We have tried our best to support the scientific facts by citations/literature and prepared the figures/legends based on our current scientific knowledge. The authors declare no conflict of interest or any financial interest.

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Authors and Affiliations

  1. Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY, 14642, USA

    Isaac K. Sundar, Hongwei Yao & Irfan Rahman

  2. Department of Biomedical Sciences, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1SB, UK

    Paul A. Kirkham

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  1. Isaac K. Sundar
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  2. Hongwei Yao
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  4. Irfan Rahman
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Correspondence to Irfan Rahman .

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  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

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Sundar, I.K., Yao, H., Kirkham, P.A., Rahman, I. (2014). Smoking, Oxidative/Carbonyl Stress, and Regulation of Redox Signaling in Lung Inflammation. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_65

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