Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke–mediated lung inflammatory response and injury

ABSTRACT Peroxiredoxin 6 (Prdx6) exerts its protective role through peroxidase activity against H2O2 and phospholipid hydroperoxides. We hypothesized that targeted disruption of Prdx6 would lead to enhanced susceptibility to cigarette smoke (CS)-mediated lung inflammation and/or emphysema in mouse lung. Prdx6 null (Prdx6−/−) mice exposed to acute CS showed no significant increase of inflammatory cell influx or any alterations in lung levels of proinflammatory cytokines compared to wild-type (WT) mice. Lung levels of antioxidant enzymes were significantly increased in acute CS-exposed Prdx6−/− compared to WT mice. Overexpressing (Prdx6+/+) mice exposed to acute CS showed significant decrease in lung antioxidant enzymes associated with increased inflammatory response compared to CS-exposed WT mice or air-exposed Prdx6−/− mice. However, chronic 6 months of CS exposure resulted in increased lung inflammatory response, mean linear intercept (Lm), and alteration in lung mechanical properties in Prdx6−/− when compared to WT mice exposed to CS. These data show that targeted disruption of Prdx6 does not lead to increased lung inflammatory response but is associated with increased antioxidants, suggesting a critical role of lung Prdx6 and several compensatory mechanisms during acute CS-induced adaptive response, whereas this protection is lost in chronic CS exposure leading to emphysema.

[1]  Sang-Gu Hwang,et al.  Peroxiredoxin 6 promotes lung cancer cell invasion by inducing urokinase-type plasminogen activator via p38 kinase, phosphoinositide 3-kinase, and Akt , 2009, Molecules and cells.

[2]  James R. Roede,et al.  Overexpression of Peroxiredoxin 6 Does Not Prevent Ethanol-Mediated Oxidative Stress and May Play a Role in Hepatic Lipid Accumulation , 2009, Journal of Pharmacology and Experimental Therapeutics.

[3]  In Sup Kil,et al.  Induction of sulfiredoxin via an Nrf2-dependent pathway and hyperoxidation of peroxiredoxin III in the lungs of mice exposed to hyperoxia. , 2009, Antioxidants & redox signaling.

[4]  S. Biswal,et al.  Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. , 2009, Free radical biology & medicine.

[5]  A. Fisher,et al.  Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[6]  James R. Roede,et al.  In vitro and in silico characterization of peroxiredoxin 6 modified by 4-hydroxynonenal and 4-oxononenal. , 2008, Chemical research in toxicology.

[7]  A. Fisher,et al.  Peroxiredoxin 6 as an antioxidant enzyme: Protection of lung alveolar epithelial type II cells from H2O2‐induced oxidative stress , 2008, Journal of cellular biochemistry.

[8]  I. Rahman,et al.  Cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[9]  I. Rahman,et al.  Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[10]  S. Ohlmeier,et al.  Does the oxidative stress in chronic obstructive pulmonary disease cause thioredoxin/peroxiredoxin oxidation? , 2008, Antioxidants & redox signaling.

[11]  P. Avila,et al.  Peroxiredoxin V Contributes to Antioxidant Defense of Lung Epithelial Cells , 2008, Lung.

[12]  S. Rhee,et al.  Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. , 2007, Kidney international. Supplement.

[13]  Irfan Rahman,et al.  Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method , 2006, Nature Protocols.

[14]  J. Mauderly,et al.  Modulators of cigarette smoke-induced pulmonary emphysema in A/J mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[15]  I. Adcock,et al.  Oxidative stress and redox regulation of lung inflammation in COPD , 2006, European Respiratory Journal.

[16]  C. Dodia,et al.  Lung phospholipid metabolism in transgenic mice overexpressing peroxiredoxin 6. , 2006, Biochimica et biophysica acta.

[17]  M. Inouye,et al.  Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice. , 2006, American journal of respiratory and critical care medicine.

[18]  A. Fisher,et al.  Peroxiredoxin 6 gene-targeted mice show increased lung injury with paraquat-induced oxidative stress. , 2006, Antioxidants & redox signaling.

[19]  A. Fisher,et al.  Transgenic mice overexpressing peroxiredoxin 6 show increased resistance to lung injury in hyperoxia. , 2006, American journal of respiratory cell and molecular biology.

[20]  N. Pleskach,et al.  Cigarette Smoke Extract Inhibits Expression of Peroxiredoxin V and Increases Airway Epithelial Permeability , 2006, Inhalation toxicology.

[21]  Arnab Majumdar,et al.  Quantitative characterization of airspace enlargement in emphysema. , 2006, Journal of applied physiology.

[22]  D. Townsend,et al.  Sulfiredoxin: a potential therapeutic agent? , 2005, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[23]  S. Kang,et al.  Variable overoxidation of peroxiredoxins in human lung cells in severe oxidative stress. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[24]  Kap-Seok Yang,et al.  Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. , 2005, Current opinion in cell biology.

[25]  L L Schulman,et al.  Correlation of lung surface area to apoptosis and proliferation in human emphysema , 2005, European Respiratory Journal.

[26]  Y. Okada,et al.  STRUCTURAL EMPHYSEMA DOES NOT CORRELATE WITH LUNG COMPLIANCE: LESSONS FROM THE MOUSE SMOKING MODEL , 2005, Experimental lung research.

[27]  A. Fisher,et al.  Lung injury and mortality with hyperoxia are increased in peroxiredoxin 6 gene-targeted mice. , 2004, Free radical biology & medicine.

[28]  Irina Petrache,et al.  Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. , 2004, The Journal of clinical investigation.

[29]  Sue Goo Rhee,et al.  Peroxiredoxin III, a Mitochondrion-specific Peroxidase, Regulates Apoptotic Signaling by Mitochondria* , 2004, Journal of Biological Chemistry.

[30]  A. Fisher,et al.  1‐Cys peroxiredoxin knock‐out mice express mRNA but not protein for a highly related intronless gene , 2003, FEBS letters.

[31]  B. Paigen,et al.  Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root. , 2003, Free radical biology & medicine.

[32]  M. Toledano,et al.  ATP-dependent reduction of cysteine–sulphinic acid by S. cerevisiae sulphiredoxin , 2003, Nature.

[33]  K. Forsman-Semb,et al.  Mice with Targeted Mutation of Peroxiredoxin 6 Develop Normally but Are Susceptible to Oxidative Stress* , 2003, Journal of Biological Chemistry.

[34]  Kap-Seok Yang,et al.  Reversing the Inactivation of Peroxiredoxins Caused by Cysteine Sulfinic Acid Formation , 2003, Science.

[35]  A. Fisher,et al.  An Antisense Oligonucleotide to 1-cys Peroxiredoxin Causes Lipid Peroxidation and Apoptosis in Lung Epithelial Cells* , 2002, The Journal of Biological Chemistry.

[36]  W. MacNee,et al.  4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. , 2002, American journal of respiratory and critical care medicine.

[37]  Y. Soini,et al.  Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis , 2002, Thorax.

[38]  S. Rhee,et al.  Peroxiredoxin, a Novel Family of Peroxidases , 2001, IUBMB life.

[39]  C. Dodia,et al.  1-Cys Peroxiredoxin, a Bifunctional Enzyme with Glutathione Peroxidase and Phospholipase A2 Activities* , 2000, The Journal of Biological Chemistry.

[40]  S. Rhee,et al.  Identification of a New Type of Mammalian Peroxiredoxin That Forms an Intramolecular Disulfide as a Reaction Intermediate* , 2000, The Journal of Biological Chemistry.

[41]  W. MacNee,et al.  Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[42]  C. Dodia,et al.  Phospholipid Hydroperoxides Are Substrates for Non-selenium Glutathione Peroxidase* , 1999, The Journal of Biological Chemistry.

[43]  C. Dodia,et al.  Cloning and expression of rat lung acidic Ca(2+)-independent PLA2 and its organ distribution. , 1998, The American journal of physiology.

[44]  C. Dodia,et al.  Cloning and expression of rat lung acidic Ca2+-independent PLA2 and its organ distribution. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[45]  S. Rhee,et al.  Characterization of a Mammalian Peroxiredoxin That Contains One Conserved Cysteine* , 1998, The Journal of Biological Chemistry.

[46]  K. Itoh,et al.  An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. , 1997, Biochemical and biophysical research communications.

[47]  K. Pinkerton,et al.  Six-month exposure of strain A/J mice to cigarette sidestream smoke: cell kinetics and lung tumor data. , 1995, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[48]  K. Pinkerton,et al.  Sidestream cigarette smoke generation and exposure system for environmental tobacco smoke studies , 1994 .

[49]  W. Thurlbeck,et al.  The effect of age on lung structure in male BALB/cNNia inbred mice. , 1984, The American journal of anatomy.