Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs

Cigarette smoking leads to alteration in cellular redox status, a hallmark in the pathogenesis of chronic obstructive pulmonary disease. This study examines the role of cigarette smoke (CS) exposure in the impairment of energy metabolism and, consequently, mitochondrial dysfunction. Male A/J mice were exposed to CS generated by a smoking machine for 4 or 8 wk. A recovery group was exposed to CS for 8 wk and allowed to recover for 2 wk. Acute CS exposure altered lung glucose metabolism, entailing a decrease in the rate of glycolysis and an increase in the pentose phosphate pathway, as evidenced by altered expression and activity of GAPDH and glucose-6-phosphate dehydrogenase, respectively. Impairment of GAPDH was found to be due to glutathionylation of its catalytic site cysteines. Metabolic changes were associated with changes in cellular and mitochondrial redox status, assessed in terms of pyridine nucleotides and glutathione. CS exposure elicited an upregulation of the expression of complexes II, III, IV, and V and of the activity of complexes II, IV, and V. Microarray analysis of gene expression in mouse lungs after exposure to CS for 8 wk revealed upregulation of a group of genes involved in metabolism, electron transfer chain, oxidative phosphorylation, mitochondrial transport and dynamics, and redox regulation. These changes occurred independently of inflammatory responses. These findings have implications for the early onset of alterations in energy and redox metabolism upon acute lung exposure to CS.

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Redox control of plant energy metabolism: The complex intertwined regulation of redox and metabolism in plant cells

The Biochemist ◽

10.1042/bio03701014 ◽

2015 ◽

Vol 37 (1) ◽

pp. 14-18

Author(s):

Toshihiro Obata ◽

Peter Geigenberger ◽

Alisdair R. Fernie

Keyword(s):

Energy Metabolism ◽

Redox Regulation ◽

Redox Status ◽

Cellular Level ◽

Fine Tuning ◽

Cellular Redox ◽

Redox Active ◽

Metabolic Activities ◽

Cellular Components ◽

Regulate Energy Metabolism

Maintenance of the cellular redox status is crucial both to keep metabolic processes running and to prevent oxidation of cellular components by reactive oxygen species under fluctuating environments. The plastid is a plant-specific organelle in which considerable redox-active reactions occur and therefore the redox status in this energy organelle, as well as that of the mitochondria, must be tightly regulated. Plants employ multiple mechanisms to actively regulate energy metabolism in response to the redox status and to integrate subcellular redox signals to orchestrate redox status at the cellular level. In this article, we describe the redox regulation of the major flux bearing reactions in these two energy organelles and survey recent advances concerning interorganellar redox communication. The sum action of this complex regulatory network allows both the fine-tuning of metabolic activities for cellular redox homoeostasis and that of redox to allow optimal metabolic function.

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p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00290.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. L496-L506 ◽

Cited By ~ 14

Author(s):

Nivedita Tiwari ◽

Amarnath S. Marudamuthu ◽

Yoshikazu Tsukasaki ◽

Mitsuo Ikebe ◽

Jian Fu ◽

...

Keyword(s):

Lung Injury ◽

Cigarette Smoke ◽

Lung Inflammation ◽

Cellular Adhesion ◽

Alveolar Epithelial Cells ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

P53 Expression ◽

Cellular Adhesion Molecule ◽

Pai 1

We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.

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Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

The Journal of Immunology ◽

10.4049/jimmunol.0903654 ◽

2010 ◽

Vol 184 (8) ◽

pp. 4460-4469 ◽

Cited By ~ 51

Author(s):

Gregory T. Motz ◽

Bryan L. Eppert ◽

Brian W. Wortham ◽

Robyn M. Amos-Kroohs ◽

Jennifer L. Flury ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Mouse Model ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Cell Activation ◽

Nk Cell ◽

Smoke Exposure ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

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Total particulate matter concentration skews cigarette smoke's gene expression profile

ERJ Open Research ◽

10.1183/23120541.00029-2016 ◽

2016 ◽

Vol 2 (4) ◽

pp. 00029-2016 ◽

Cited By ~ 5

Author(s):

Anna Dvorkin-Gheva ◽

Gilles Vanderstocken ◽

Ali Önder Yildirim ◽

Corry-Anke Brandsma ◽

Ma'en Obeidat ◽

...

Keyword(s):

Gene Expression ◽

Particulate Matter ◽

Cigarette Smoke ◽

Gene Expression Profile ◽

Expression Profile ◽

Smoke Exposure ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Total Particulate Matter ◽

Xenobiotic Detoxification

Exposure of small animals to cigarette smoke is widely used as a model to study the pathogenesis of chronic obstructive pulmonary disease. However, protocols and exposure systems utilised vary substantially and it is unclear how these different systems compare.We analysed the gene expression profile of six publically available murine datasets from different cigarette smoke-exposure systems and related the gene signatures to three clinical cohorts.234 genes significantly regulated by cigarette smoke in at least one model were used to construct a 55-gene network containing 17 clusters. Increasing numbers of differentially regulated clusters were associated with higher total particulate matter concentrations in the different datasets. Low total particulate matter-induced genes mainly related to xenobiotic/detoxification responses, while higher total particulate matter activated immune/inflammatory processes in addition to xenobiotic/detoxification responses. To translate these observations to the clinic, we analysed the regulation of the revealed network in three human cohorts. Similar to mice, we observed marked differences in the number of regulated clusters between the cohorts. These differences were not determined by pack-year.Although none of the experimental models exhibited a complete alignment with any of the human cohorts, some exposure systems showed higher resemblance. Thus, depending on the cohort, clinically observed changes in gene expression may be mirrored more closely by specific cigarette smoke exposure systems. This study emphasises the need for careful validation of animal models.

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Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

Infection and Immunity ◽

10.1128/iai.00165-08 ◽

2008 ◽

Vol 76 (8) ◽

pp. 3481-3490 ◽

Cited By ~ 34

Author(s):

Paul J. Christensen ◽

Angela M. Preston ◽

Tony Ling ◽

Ming Du ◽

W. Bradley Fields ◽

...

Keyword(s):

Cigarette Smoke ◽

Pulmonary Inflammation ◽

Airflow Obstruction ◽

Smoke Exposure ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Respiratory Pathogens ◽

Obstructive Pulmonary Disease ◽

Immunocompetent Mice

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.

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Cigarette smoke and CFTR: implications in the pathogenesis of COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00039.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. L530-L541 ◽

Cited By ~ 87

Author(s):

Andras Rab ◽

Steven M. Rowe ◽

S. Vamsee Raju ◽

Zsuzsa Bebok ◽

Sadis Matalon ◽

...

Keyword(s):

Cystic Fibrosis ◽

Cigarette Smoke ◽

Inflammatory Responses ◽

Common Mechanism ◽

Chronic Obstructive ◽

Respiratory Disorder ◽

Chronic Infections ◽

Gene Encoding ◽

Obstructive Pulmonary Disease ◽

Copd Patients

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder consisting of chronic bronchitis and/or emphysema. COPD patients suffer from chronic infections and display exaggerated inflammatory responses and a progressive decline in respiratory function. The respiratory symptoms of COPD are similar to those seen in cystic fibrosis (CF), although the molecular basis of the two disorders differs. CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene encoding a chloride and bicarbonate channel (CFTR), leading to CFTR dysfunction. The majority of COPD cases result from chronic oxidative insults such as cigarette smoke. Interestingly, environmental stresses including cigarette smoke, hypoxia, and chronic inflammation have also been implicated in reduced CFTR function, and this suggests a common mechanism that may contribute to both the CF and COPD. Therefore, improving CFTR function may offer an excellent opportunity for the development of a common treatment for CF and COPD. In this article, we review what is known about the CF respiratory phenotype and discuss how diminished CFTR expression-associated ion transport defects may contribute to some of the pathological changes seen in COPD.

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Peroxisome proliferator-activated receptor-γ inhibits cigarette smoke solution-induced mucin production in human airway epithelial (NCI-H292) cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00388.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. L84-L90 ◽

Cited By ~ 38

Author(s):

Sung Yong Lee ◽

Eun Joo Kang ◽

Gyu Young Hur ◽

Ki Hwan Jung ◽

Hye Cheol Jung ◽

...

Keyword(s):

Cigarette Smoke ◽

Inflammatory Responses ◽

Cigarette Smoke Exposure ◽

Etiologic Factor ◽

Peroxisome Proliferator ◽

Cell Hyperplasia ◽

Peroxisome Proliferator Activated Receptor ◽

Mucin Production ◽

Ppar Γ ◽

Anti Inflammatory

The main etiologic factor for chronic bronchitis is cigarette smoke. Exposure to cigarette smoke is reported to induce goblet cell hyperplasia and mucus production. Mucin synthesis in airways has been reported to be regulated by the EGFR system. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the ligand-activated nuclear receptor superfamily. PPAR-γ is implicated in anti-inflammatory responses, but mechanisms underlying these varied roles remain ill-defined. Recently, reports have shown that upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) might be one of the mechanisms through which PPAR-γ agonists exert their anti-inflammatory actions. However, no data are available on the role of PPAR-γ in smoke-induced mucin production. In this study, we investigated the effect of PPAR-γ agonist (rosiglitazone) on smoke-induced mucin production in NCI-H292 cells. Exposure to cigarette smoke causes a significant decrease in PTEN expression and increases dose-dependent EGFR-specific tyrosine phosphorylation, resulting in MUC5AC mucin production in NCI-H292 cells. PPAR-γ agonists or specific inhibitors of phosphoinositide 3-kinase exert inhibition of cigarette smoke-induced mucin production, with the upregulation of PTEN signaling and downregulation of Akt expression. This study demonstrates that PPAR-γ agonist functions as a regulator of epithelial cell inflammation that may result in reduction of mucin-producing cells in airway epithelium.

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TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00134.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. L295-L304 ◽

Cited By ~ 109

Author(s):

Charalambos Michaeloudes ◽

Maria B. Sukkar ◽

Nadia M. Khorasani ◽

Pankaj K. Bhavsar ◽

Kian Fan Chung

Keyword(s):

Smooth Muscle ◽

Antioxidant Enzymes ◽

Airway Smooth Muscle ◽

Manganese Superoxide Dismutase ◽

Redox Regulation ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Chronic Obstructive ◽

Airway Smooth Muscle Cells ◽

Nadph Oxidase 4

Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.

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Integrating 3-omics data analyze rat lung tissue of COPD states and medical intervention by delineation of molecular and pathway alterations

Bioscience Reports ◽

10.1042/bsr20170042 ◽

2017 ◽

Vol 37 (3) ◽

Cited By ~ 9

Author(s):

Jiansheng Li ◽

Peng Zhao ◽

Liping Yang ◽

Ya Li ◽

Yange Tian ◽

...

Keyword(s):

Oxidative Stress ◽

Arachidonic Acid ◽

Energy Metabolism ◽

Molecular Mechanisms ◽

Acid Metabolism ◽

Inflammatory Responses ◽

Medical Intervention ◽

Arachidonic Acid Metabolism ◽

Chronic Obstructive ◽

Therapeutic Effects

Chronic obstructive pulmonary disease (COPD) is a serious health problem. However, the molecular pathogenesis of COPD remains unknown. Here, we explored the molecular effects of cigarette smoke and bacterial infection in lung tissues of COPD rats. We also investigated therapeutic effects of aminophylline (APL) on the COPD rats and integrated transcriptome, proteome, and metabolome data for a global view of molecular mechanisms of COPD progression. Using molecular function and pathway analyses, the genes and proteins regulated in COPD and APL-treated rats were mainly attributed to oxidoreductase, antioxidant activity, energy and fatty acid metabolism. Furthermore, we identified hub proteins such as Gapdh (glyceraldehyde-3-phosphate dehydrogenase), Pkm (pyruvate kinase isozymes M1/M2), and Sod1 (superoxide dismutase 1), included in energy metabolism and oxidative stress. Then, we identified the significantly regulated metabolic pathways in lung tissues of COPD- and APL-treated rats, such as arachidonic acid, linoleic acid, and α-linolenic acid metabolism, which belong to the lipid metabolism. In particular, we picked the arachidonic acid metabolism for a more detailed pathway analysis of transcripts, proteins, and metabolites. We could observe an increase in metabolites and genes involved in arachidonic acid metabolism in COPD rats and the decrease in these in APL-treated rats, suggesting that inflammatory responses were up-regulated in COPD rats and down-regulated in APL-treated rats. In conclusion, these system-wide results suggested that COPD progression and its treatment might be associated with oxidative stress, lipid and energy metabolism disturbance. Additionally, we demonstrated the power of integrated omics for the elucidation of genes, proteins, and metabolites’ changes and disorders that were associated with COPD.

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