Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease☆
Introduction
Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem and is the fourth most common cause of death in the developed countries. It is a disabling condition associated with progressive breathlessness. COPD will account for over six million deaths per year and is predicted to increase from the sixth to the third leading cause of death by 2020 worldwide. In America, COPD affects 9% of residents aged 60 years and above, and is ranked the fourth in the recent morbidity survey of the elderly population. It is estimated that approximately 23.4 million people in the United States have COPD and the health burden is $36.1 billion per year. The burden of COPD for the patient is high as patients experience a poorer quality of life, suffer from comorbidites (3.7 comorbidities per patient), and direct healthcare amounted to 20.9 billion dollars in the United States in 2004.
Cigarette smoke is the major risk factor for the development of COPD. It is likely to account for ~ 80–90% of COPD cases in the United States (Sethi and Rochester, 2000). Cigarette smoke contains an estimated 1015–1017 oxidants/free radicals and ~ 4700 different chemical compounds, including reactive aldehydes and quinones, per puff (Church and Pryor, 1985). COPD (emphysema and chronic bronchitis) is characterized by accelerated decline in lung function, inflammation and premature aging of the lung. However, only 10–20% of the smokers develop COPD pointing to an additional risk factor, such as genetic susceptibility, e.g., the polymorphisms in genes coding for (anti-) proteases like alpha-1 antitrypsin (1AAT), a disintegrin and metalloproteinase 33 (ADAM33), or antioxidant superoxide dismutase (SOD), and proinflammatory mediators tumor necrosis factor-α (TNF-α) (Harrison et al., 1997, Keatings et al., 2000, Sandford et al., 2001, Kucukaycan et al., 2002, Celedon et al., 2004, Young et al., 2006). Other noxious environmental gases/particles such as NO2, SO2, and particulate matters, as well as exposure to second hand tobacco smoke and biomass fuel can also cause oxidative stress and trigger inflammatory responses in the lungs of a susceptible population. Cessation of smoking reduces progression of the disease only if applied early and has little effect after significant symptoms ensues. At present, no effective treatment exists to halt the decline of lung function in smokers who get the disease. This in turn reflects a lack of understanding of the specific cellular and biochemical pathways triggered in the lung by tobacco smoke. Thus, it is essential that COPD research should focus on improving our understanding of the specific cellular and biochemical injury induced by tobacco smoke within the lung. Most treatments for COPD are mainly palliative, and no single therapy exists that can halt the decline in lung function or progressive destruction of the airways. The mainstays of pharmacotherapy are bronchodilators (to relieve the symptoms of bronchoconstriction), corticosteroids (to reduce the airway inflammation), and combination of bronchodilators with corticosteroids. However, current corticosteroid therapy in COPD is poorly effective (Barnes et al., 2004). This has prompted an intense search for new anti-inflammatory therapeutic targets based on a better understanding of the underlying pathophysiology of COPD.
Section snippets
Pathogenesis
COPD is characterized by airflow limitation that is usually irreversible and progressive, and associated with an abnormal inflammatory response of the lung to noxious particles or gases (Rabe et al., 2007). COPD can be classified into four classes of severity based on lung function [GOLD Guidelines]. Emphysema, chronic bronchitis with airway obstruction, and small airways disease are the distinct phenotypes of COPD, but most patients show a combination of different phenotypes. Emphysema is
Oxidative and aldehyde/carbonyl stress in COPD
Formation of reactive and unstable free radicals such as superoxide anion (O2•ˉ), nitric oxide, peroxynitrite (ONOO-) and hydroxyl radicals (•OH) lead to a series of chain reactions resulting in uncontrolled (if not ablated) tissue destruction as a result of oxidation. The importance of oxidative stress has been confirmed by several studies that have identified the presence of oxidative stress/free radical biomarkers in patients with COPD. Increased level of 8-hydroxy-deoxyguanosine was
Inflammatory response in COPD
The chronic inflammation of COPD is characterized by an accumulation of neutrophils, macrophages, B-cells, lymphoid aggregates, CD4+, CD8+ T-cells, and eosinophils, particularly in the small airways (Turato et al., 2002, Hogg, 2004a; Saha and Brightling, 2006, Siva et al., 2007) (Fig. 2) and the degree of inflammation increases with the severity of disease as classified by the GOLD guidelines (Hogg et al., 2004b).
Epigenetics in pathogenesis of COPD
Epigenetics refers to heritable changes in gene expression without the alteration of DNA sequence. However, it is controlled by post-translational modifications in histone proteins and DNA. These modifications include chromatin remodeling (histone acetylation, methylation, ubiquination, phosphorylation, and sumoylation) and DNA methylation.
Conclusions and future directions
Oxidative stress is critical for lung inflammatory response to cigarette smoke/environmental pollutants through the upregulation of redox-sensitive transcription factors, and induction of autophagy and unfolded protein response. Hence, development of antioxidants/thiol agents or other pharmacological agents, such as enzyme mimetics-ECSOD, Nrf2 activator or reversing its post-translational modifications by aldehyde dehydrogenases/reducatases to boost the endogenous antioxidant system, could be
Acknowledgments
This study was supported by NIH 1R01HL085613, 1R01HL097751, 1R01HL092842, and NIEHS Environmental Health Sciences Center grant ES01247. We thank Dr. Saravanan Rajendrasozhan for useful discussions.
References (229)
- et al.
Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction
Biochem. Biophys. Res. Commun.
(2010) - et al.
SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: role of resveratrol
Biochem. Biophys. Res. Commun.
(2010) - et al.
Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase
Lancet
(2004) - et al.
Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4
Chest
(2003) - et al.
CD8+ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure
Exp. Mol. Pathol.
(2007) - et al.
Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries
Biochem. Pharmacol.
(2000) - et al.
The diverse functions of histone acetyltransferase complexes
Trends Genet.
(2003) - et al.
Nrf2 protects against airway disorders
Toxicol. Appl. Pharmacol.
(2010) - et al.
The role of nuclear factor-kappa B in pulmonary diseases
Chest
(2000) - et al.
Gene cloning, RNA distribution, and functional expression of mCX3CR1, a mouse chemotactic receptor for the CX3C chemokine fractalkine
Biochem. Biophys. Res. Commun.
(1998)
Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1
J. Biol. Chem.
CXCR3 and CCR5 chemokines in induced sputum from patients with COPD
Chest
PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress
J. Biol. Chem.
Cytokines and therapy in COPD: a promising combination?
Chest
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial
Lancet
IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family
J. Allergy Clin. Immunol.
Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease
Trends Pharmacol. Sci.
Markers of disease severity in chronic obstructive pulmonary disease
Pulm. Pharmacol. Ther.
Phosphatase inhibition leads to histone deacetylases 1 and 2 phosphorylation and disruption of corepressor interactions
J. Biol. Chem.
Missing pieces in the NF-kappaB puzzle
Cell
Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome
Am. J. Pathol.
An integrated stress response regulates amino acid metabolism and resistance to oxidative stress
Mol. Cell
Endoplasmic reticulum stress induced by aqueous extracts of cigarette smoke in 3 T3 cells activates the unfolded-protein-response-dependent PERK pathway of cell survival
Free Radic. Biol. Med.
Pathophysiology of airflow limitation in chronic obstructive pulmonary disease
Lancet
Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress preconditioning is mediated by ERK1/2 activation
J. Biol. Chem.
Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD
Arch. Biochem. Biophys.
Transcription: gene control by targeted histone acetylation
Curr. Biol.
Impact of protein acetylation in inflammatory lung diseases
Pharmacol. Ther.
Cigarette smoke-induced loss of nuclear HDAC2 is associated with chronic inflammation and emphysema in A/J mice
Am. J. Respir. Crit. Care Med.
HDAC2 degradation is associated with increased hyperphosphorylation and a proteasome-dependent mechanism in response to cigarette smoke in macrophages
Am. J. Respir. Crit. Care Med.
Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke
Am. J. Respir. Cell Mol. Biol.
CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration
J. Immunol.
Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity
Eur. J. Immunol.
Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress
J. Neurosci.
Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents
J. Clin. Invest.
A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression
Nature
Reversing histone methylation
Nature
Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice
J. Clin. Invest.
TRPA1 is a major oxidant sensor in murine airway sensory neurons
J. Clin. Invest.
NRF2 protects mice from cigarette smoke-induced emphysema
FASEB J.
Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation
Am. J. Respir. Cell Mol. Biol.
Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease
J. Clin. Invest.
Nonredundant functions of alphabeta and gammadelta T cells in acrolein-induced pulmonary pathology
Toxicol. Sci.
Cigarette smoke-induced pulmonary inflammation, but not airway remodelling, is attenuated in chemokine receptor 5-deficient mice
Clin. Exp. Allergy
Sirtuin 1, an oxidant sensitive deacetylase, is posttraslationally modified and degraded by the proteasome in response to cigarette smoke in lung epithelial cells
FASEB J.
SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress
FASEB J.
IL-32, a novel proinflammatory cytokine in chronic obstructive pulmonary disease
Am. J. Respir. Crit. Care Med.
Increased MCP-1 and MIP-1beta in bronchoalveolar lavage fluid of chronic bronchitics
Eur. Respir. J.
Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha
Mol. Cell. Biol.
The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD)
Hum. Mol. Genet.
Cited by (0)
- ☆
Notice. The views expressed in this paper are those of the authors. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.