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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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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