A comprehensive analysis of oxidative stress in the ozone-induced lung inflammation mouse model.

Ozone is an oxidizing environmental pollutant that contributes significantly to respiratory health. Exposure to increased levels of ozone has been associated with worsening of symptoms of patients with asthma and COPD (chronic obstructive pulmonary disease). In the present study, we investigated the acute and chronic effects of ozone exposure-induced oxidative stress-related inflammation mechanics in mouse lung. In particular, we investigated the oxidative stress-induced effects on HDAC2 (histone deacetylase 2) modification and activation of the Nrf2 (nuclear factor erythroid-related factor 2) and HIF-1α (hypoxia-inducible factor-1α) signalling pathways. Male C57BL/6 mice were exposed to ozone (3 p.p.m.) for 3 h a day, twice a week for a period of 1, 3 or 6 weeks. Control mice were exposed to normal air. After the last exposure, mice were killed for BAL (bronchoalveolar lavage) fluid and lung tissue collection. BAL total cell counts were elevated at all of the time points studied. This was associated with increased levels of chemokines and cytokines in all ozone-exposed groups, indicating the presence of a persistent inflammatory environment in the lung. Increased inflammation and Lm (mean linear intercept) scores were observed in chronic exposed mice, indicating emphysematous changes were present in lungs of chronic exposed mice. The antioxidative stress response was active (indicated by increased Nrf2 activity and protein) after 1 week of ozone exposure, but this ability was lost after 3 and 6 weeks of ozone exposure. The transcription factor HIF-1α was elevated in 3- and 6-week ozone-exposed mice and this was associated with increased gene expression levels of several HIF-1α target genes including Hdac2 (histone deacetylase 2), Vegf (vascular endothelial growth factor), Keap1 (kelch-like ECH-associated protein 1) and Mif (macrophage migration inhibitory factor). HDAC2 protein was found to be phosphorylated and carbonylated in nuclear and cytoplasm fractions, respectively, and was associated with a decrease in DNA-binding activity and protein expression of HDAC2. Decreased HDAC2 activity, most likely a direct result of protein modification, in combination with the loss of the antioxidative stress response and activation of the HIF-1α pathway, contribute to the inflammatory response and emphysema observed in ozone-exposed mice.

[1]  V. Nizet,et al.  Hypoxia potentiates allergen induction of HIF-1α, chemokines, airway inflammation, TGF-β1, and airway remodeling in a mouse model. , 2013, Clinical immunology.

[2]  Min Zhang,et al.  IL-17A Modulates Oxidant Stress-Induced Airway Hyperresponsiveness but Not Emphysema , 2013, PloS one.

[3]  Tae-Yoon Kim,et al.  Superoxide dismutase 3 controls adaptive immune responses and contributes to the inhibition of ovalbumin-induced allergic airway inflammation in mice. , 2012, Antioxidants & redox signaling.

[4]  O. Hankinson,et al.  HIF-1 expression is associated with CCL2 chemokine expression in airway inflammatory cells: implications in allergic airway inflammation , 2012, Respiratory Research.

[5]  A. Dai,et al.  [The expression of hypoxia-inducible factor-1alpha and its hydroxylases in pulmonary arteries of patient with chronic obstructive pulmonary disease]. , 2012, Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology.

[6]  Qi Li,et al.  Regulation of cigarette smoke‐mediated mucin expression by hypoxia‐inducible factor‐1α via epidermal growth factor receptor‐mediated signaling pathways , 2012, Journal of applied toxicology : JAT.

[7]  Ian M Adcock,et al.  Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. , 2012, American journal of respiratory and critical care medicine.

[8]  J. W. Lee,et al.  Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium , 2011, The Journal of pathology.

[9]  S. Biswal,et al.  Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress , 2011, Biochemical and biophysical research communications.

[10]  Min Zhang,et al.  A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice. , 2011, American journal of physiology. Lung cellular and molecular physiology.

[11]  I. Rahman,et al.  Protein kinase CK2-mediated phosphorylation of HDAC2 regulates co-repressor formation, deacetylase activity and acetylation of HDAC2 by cigarette smoke and aldehydes. , 2010, Archives of biochemistry and biophysics.

[12]  F. Fitzpatrick,et al.  Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function* , 2010, The Journal of Biological Chemistry.

[13]  I. Adcock,et al.  Hypoxia-inducible Factor 1α Induces Corticosteroid-insensitive Inflammation via Reduction of Histone Deacetylase-2 Transcription* , 2009, The Journal of Biological Chemistry.

[14]  Kazuhiro Ito,et al.  Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. , 2009, Biochemical and biophysical research communications.

[15]  Maud Martin,et al.  Class IIa histone deacetylases: conducting development and differentiation. , 2009, The International journal of developmental biology.

[16]  A. Resende,et al.  Involvement of nitric oxide in acute lung inflammation induced by cigarette smoke in the mouse. , 2009, Nitric oxide : biology and chemistry.

[17]  Hongwei Yao,et al.  Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. , 2009, American journal of respiratory cell and molecular biology.

[18]  Y. Nasuhara,et al.  Down-regulated Nf-e2–related Factor 2 in Pulmonary Macrophages of Aged Smokers and Patients with Chronic Obstructive Pulmonary Disease Materials and Methods Collection of Human Alveolar Macrophages , 2022 .

[19]  L. C. Pôrto,et al.  Oxidative stress in mouse plasma and lungs induced by cigarette smoke and lipopolysaccharide. , 2008, Environmental research.

[20]  Deepti Malhotra,et al.  Decline in Nrf2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, Dj-1 , 2022 .

[21]  I. Adcock,et al.  Modulation of ozone-induced airway hyperresponsiveness and inflammation by interleukin-13 , 2008, European Respiratory Journal.

[22]  T. Griffin,et al.  Oxidative Stress and Covalent Modification of Protein with Bioactive Aldehydes* , 2008, Journal of Biological Chemistry.

[23]  B. Crestani,et al.  Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema , 2008, Thorax.

[24]  S. Goya,et al.  Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17 , 2008, The Journal of experimental medicine.

[25]  J. Davie,et al.  Differential Distribution of Unmodified and Phosphorylated Histone Deacetylase 2 in Chromatin* , 2007, Journal of Biological Chemistry.

[26]  I. Adcock,et al.  Role of TLR2, TLR4, and MyD88 in murine ozone-induced airway hyperresponsiveness and neutrophilia. , 2007, Journal of applied physiology.

[27]  D. Mannino,et al.  International variation in the prevalence of COPD (The BOLD Study): a population-based prevalence study , 2007, The Lancet.

[28]  P. Massion,et al.  Association of progressive structural changes in the bronchial epithelium with subepithelial fibrous remodeling: A potential role for hypoxia , 2007, Virchows Archiv.

[29]  I. Adcock,et al.  Attenuation of Ozone-Induced Airway Inflammation and Hyper-Responsiveness by c-Jun NH2 Terminal Kinase Inhibitor SP600125 , 2007, Journal of Pharmacology and Experimental Therapeutics.

[30]  W. M. Foster,et al.  Ozone and pulmonary innate immunity. , 2007, Proceedings of the American Thoracic Society.

[31]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[32]  I. Adcock,et al.  Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. , 2006, American journal of respiratory and critical care medicine.

[33]  I. Rahman,et al.  Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[34]  C. D. Mathers,et al.  Chronic obstructive pulmonary disease: current burden and future projections , 2006, European Respiratory Journal.

[35]  Michelle L. Bell,et al.  A Meta-Analysis of Time-Series Studies of Ozone and Mortality With Comparison to the National Morbidity, Mortality, and Air Pollution Study , 2005, Epidemiology.

[36]  I. Adcock,et al.  Decreased histone deacetylase activity in chronic obstructive pulmonary disease. , 2005, The New England journal of medicine.

[37]  M. Déry,et al.  Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. , 2005, The international journal of biochemistry & cell biology.

[38]  S. Reddy,et al.  Gene expression profiling of NRF2-mediated protection against oxidative injury. , 2005, Free radical biology & medicine.

[39]  F. Dominici,et al.  Ozone and short-term mortality in 95 US urban communities, 1987-2000. , 2004, JAMA.

[40]  Joel Schwartz,et al.  Acute effects of ozone on mortality from the "air pollution and health: a European approach" project. , 2004, American journal of respiratory and critical care medicine.

[41]  I. Adcock,et al.  Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase , 2004, The Lancet.

[42]  Masayuki Yamamoto,et al.  Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Pauwels,et al.  Chronic obstructive pulmonary disease: molecular and cellularmechanisms , 2003, European Respiratory Journal.

[44]  I. Adcock,et al.  Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1β-Induced Histone H4 Acetylation on Lysines 8 and 12 , 2000, Molecular and Cellular Biology.

[45]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[46]  J. Schwartz,et al.  Short term effects of air pollution on health: a European approach using epidemiologic time series data: the APHEA protocol. , 1996, Journal of epidemiology and community health.

[47]  H. R. Anderson,et al.  Short-term effects of air pollution on health: a European approach using epidemiological time-series data. The APHEA project: background, objectives, design. , 1995, The European respiratory journal.

[48]  S. Marklund.  Extracellular superoxide dismutase in human tissues and human cell lines. , 1984, The Journal of clinical investigation.

[49]  S. Marklund,et al.  Human copper-containing superoxide dismutase of high molecular weight. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Crapo,et al.  Superoxide dismutase and pulmonary oxygen toxicity. , 1974, The American journal of physiology.

[51]  I. Fridovich,et al.  Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. , 1973, The Journal of biological chemistry.

[52]  E. R. Mcfadden,et al.  Arterial-blood gas tension in asthma. , 1968, The New England journal of medicine.