Cigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD

Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. Aberrant expression or activity of CatS has been implicated in a variety of diseases, including arthritis, cancer, cardiovascular, and lung diseases. However, little is known about the effect of cigarette smoking on both CatS expression and activity, as well as its role in smoking-related lung diseases. Here, we evaluated the expression and activity of human CatS in lung tissues from never-smokers and smokers with or without COPD. Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.

Download Full-text

Effect of vitamin D3 on lung damage induced by cigarette smoke in mice

Open Medicine ◽

10.1515/med-2019-0096 ◽

2019 ◽

Vol 14 (1) ◽

pp. 827-832

Author(s):

Xin Zheng ◽

Nini Qu ◽

Lina Wang ◽

Guoli Wang ◽

Rui Jiao ◽

...

Keyword(s):

Cigarette Smoking ◽

Cigarette Smoke ◽

Vitamin D3 ◽

Lung Diseases ◽

Low Dose ◽

Lung Damage ◽

Over Expression ◽

Ifn Γ ◽

Airway Model ◽

Morphological Assessment

AbstractCigarette smoking is known to induce serious lung diseases, but there is not an effective method to solve this problem. The present study investigated vitamin D3 on over-expression of CXCR3 and CXCL10 in mice induced by cigarette smoking. A pulmonary airway model was designed, and morphological assessment of emphysema, IL-4, IFN-γ and CXCL10 concentration in bronchoalveolar lavage fluids, expression of CXCR3 and CXCL10 were detected. Emphysema of the mice only exposed to cigarette smoke was significant, and concentration of IL-4, IFN-γ and CXCL10 was also increased. In addition, CXCR3 and CXCL10 were over-expressed. The degree of emphysema, concentration of IL-4, IFN-γ and CXCL10, and expression of CXCR3 and CXCL10 in mice administrated with low dose vitamin D3 were similar to the normally treated mice. Low dose of vitamin D3 can effectively protect the lung from the damage induced by cigarette smoke.

Download Full-text

Exposure to the gut microbiota from cigarette smoke-exposed mice exacerbates cigarette smoke extract-induced inflammation in zebrafish larvae

10.1101/2021.09.20.461170 ◽

2021 ◽

Author(s):

Simone Morris ◽

Kathryn Wright ◽

Vamshikrishna Malyla ◽

Warwick J Britton ◽

Philip M Hansbro ◽

...

Keyword(s):

Cigarette Smoking ◽

Gut Microbiota ◽

Cigarette Smoke ◽

Cigarette Smoke Extract ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Zebrafish Larvae ◽

Modifying Factors ◽

Physiological Processes ◽

Inflammatory Phenotype

AbstractCigarette smoke (CS)-induced inflammation leads to a range of diseases including chronic obstructive pulmonary disease and cancer. Environmental factors including gut microbiota make up are major modifying factors that determine the severity of cigarette smoke-induced pathology. Adult zebrafish display increased inflammatory cytokine transcription when exposed to cigarette smoke extract (CSE) but incongruously do not produce a mucosal leukocytic inflammation phenotype. Zebrafish embryos and larvae have been used to model the effects of cigarette smoking on a range of physiological processes and offer an amenable platform for screening modifiers of cigarette smoke-induced pathologies. Here we exposed zebrafish larvae to CSE and showed that it was toxic and we characterised a CSE-induced leukocytic inflammatory phenotype with increased neutrophilic and macrophage responses. The CSE-induced phenotype was exacerbated by co-exposure to microbiota from the faeces of CS-exposed mice, but not control mice. Microbiota could be recovered from the gut of zebrafish and studied in isolation. This demonstrates the utility of the zebrafish-CSE exposure platform for identifying environmental modifiers of cigarette smoking-associated pathology and demonstrates that the CS-exposed mouse gut microbiota potentiates the inflammatory effects of CSE across host species.

Download Full-text

Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7573 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7573-7573

Author(s):

V. A. Miller ◽

G. J. Riely ◽

M. G. Kris ◽

D. Rosenbaum ◽

J. Marks ◽

...

Keyword(s):

Cigarette Smoking ◽

Mutational Analysis ◽

Smoking History ◽

Egfr Mutations ◽

Molecular Testing ◽

Kras Mutations ◽

Exon 2 ◽

Significant Difference ◽

Never Smokers ◽

Lung Adenocarcinomas

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.

Download Full-text

Is cigarette smoke associated with increased catabolism of gemcitabine in patients with advanced solid tumors?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2602 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2602-2602

Author(s):

Meaghan Working O'Malley ◽

Stephanie Daignault ◽

Patrick N. Healy ◽

Lindsay A. Schmidt ◽

Nithya Ramnath

Keyword(s):

Logistic Regression ◽

Cigarette Smoking ◽

Small Sample Size ◽

Plasma Concentrations ◽

Small Sample ◽

Stage Iii ◽

Disease Stage ◽

Smoking History ◽

Unknown Primary ◽

Never Smokers

2602 Background: Cigarette smoking can accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent. Reduced drug levels may lead to undertreatment in smokers and, conversely, increased treatment-related neutropenia in nonsmokers. Methods: An IRB-approved retrospective chart review was performed on 151 patients with solid tumor malignancies who received gemcitabine alone or in combination with oral chemotherapy agents from July 1, 2009 to June 30, 2011 at the University of Michigan. Using logistic regression, we compared toxicity, including neutropenia, and smoking history measured in pack-years in smokers vs. nonsmokers to ascertain whether cigarette smoking is an independent factor predictive of toxicity to gemcitabine. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary (15.2%). Most patients had advanced disease (stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; n=107), 77.6% patients had stage III-IV disease. Within the PB cohort, most patients were “ever” smokers as compared to “never” smokers (60.7% vs. 39.3%). Logistic regression of this cohort showed that current smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers (OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with higher pack-year history: smokers with >50 pack-years had even less neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-1.699]). Further statistical analysis of subgroups was not performed due to small sample size. Conclusions: Smokers with pancreatobiliary malignancies receiving gemcitabine had less treatment-related neutropenia as compared to never smokers, a finding that was more pronounced as pack-years increased. Decreased toxicity, including neutropenia, may be due to increased metabolism and drug clearance as a result of smoking. This may lead to potential undertreatment of smokers and, conversely, increased treatment-related toxicity in never smokers. A prospective clinical trial is needed to further elucidate this correlation, and is currently being designed.

Download Full-text

The Relationship Between Cigarette Smoking and Biomarkers of Exposure Across Two Study Centers in Europe

The Open Biomarkers Journal ◽

10.2174/1875318301003010021 ◽

2010 ◽

Vol 3 (1) ◽

pp. 21-25 ◽

Cited By ~ 1

Author(s):

Frazer J. Lowe ◽

Evan O. Gregg ◽

Antonella Bassi ◽

Riccardo Puntoni

Keyword(s):

Cigarette Smoking ◽

Cigarette Smoke ◽

Significant Relationship ◽

Urine Samples ◽

Parent Molecule ◽

Biomarkers Of Exposure ◽

Never Smokers ◽

The Relationship ◽

Biomarker Data

The relationship between biomarkers of exposure to cigarette smoke in 24h urine samples collected from groups of 80 smokers (44 males, 36 females) and 40 never smokers (17 males, 23 females) at two centers in Europe was studied. Eight biomarkers (nicotine, cotinine, hydroxycotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and all of the respective glucuronide conjugates) were measured. Subjects from the two centers were pooled and biomarker data analyzed according to the machine smoked tar yield of the brand each subject smoked and the recorded number of cigarettes smoked per day (CPD). A statistically significant relationship between CPD and all of the biomarkers analyzed was found. Smokers of less than 11 CPD had the lowest mean 24h urinary concentrations for all biomarkers measured. However, if the amount of constituent obtained from each cigarette smoked was calculated, then the amount of nicotine obtained per cigarette was highest in this group although the variation was also greatest for this group. The amount of NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone, the parent molecule of NNAL) obtained per cigarette was not statistically significantly different across all groups. In conclusion, these results confirm the reliability of 24h urinary total nicotine and NNAL concentrations as biomarkers of exposure to specific cigarette smoke constituents across two centers in Europe. These measurements may provide an objective alternative to CPD when grouping smokers for are studies of other endpoints.

Download Full-text

Abstract P063: Cigarette Smoking and Neuroimaging Indices of Cerebrovascular Health in a Population-based Cohort of Middle-aged Adults

Circulation ◽

10.1161/circ.133.suppl_1.p063 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Martine Elbejjani ◽

David R Jacobs ◽

Reto Auer ◽

Nick R Bryan ◽

Lenore J Launer

Keyword(s):

Cigarette Smoking ◽

Fractional Anisotropy ◽

Population Based ◽

Smoking History ◽

Middle Aged ◽

Parietal Lobes ◽

Cerebrovascular Health ◽

Former Smokers ◽

Never Smokers ◽

Middle Aged Adults

Introduction: Several studies report an association between cigarette smoking and dementia. One proposed hypothesis is that smoking leads to adverse cognitive and brain changes through vascular pathways. To date, few data exist on the link between smoking and vascular brain measures. We examined, in a population-based middle-aged cohort, the association of history of cigarette smoking with three indicators of cerebrovascular health: (i) white matter (WM) integrity measured using WM-fractional anisotropy, (ii) abnormal WM volume, and (iii) cerebral blood flow (CBF) in the gray matter. We focused on lobar measures of these indicators to detect whether specific regional cerebrovascular indicators are differently related to smoking. Hypothesis: We assessed the hypothesis that smoking history is associated with more adverse cerebrovascular measures (lower fractional anisotropy, larger abnormal WM volumes, and lower CBF). Methods: Data come from the Coronary Artery Risk Development in Young Adults CARDIA-brain magnetic resonance imaging sub-study (n=538). Brain measures and self-reported smoking history were obtained at the 25th year follow-up (mean age=50). We used linear (for CBF and WM-fractional anisotropy) and multinomial logistic (for abnormal WM volume) regression models, adjusted for potential confounders (including vascular and lifestyle risk factors and medical conditions). Results: Compared to never-smokers, current smokers had lower WM-fractional anisotropy in all brain lobes (-0.005 lower fractional anisotropy in the occipital lobe and -0.006 in the other lobes; p<0.05). Smoking history was also associated with larger abnormal WM volumes: Compared to never-smokers, smokers and/or former-smokers had patterns of larger abnormal WM volumes in all lobes, with pronounced associations observed in the frontal lobe wherein smokers and former-smokers had up to twice the risk of having larger abnormal frontal WM volumes as never-smokers (p<0.05). Smoking history was associated with lower CBF in the occipital (-2.89 ml/100g/min (95%CI=-5.43, -0.36); p=0.03) and parietal lobes (-3.31 (95%CI=-5.91, -0.71); p=0.01). Conclusions: In this cohort of middle-aged adults, associations between smoking and adverse WM measures were observed in all brain lobes, whereas associations of smoking with CBF were localized in the occipital and parietal lobes. This localization may reflect a link between smoking and blood flow processes related to sensory-cognitive networks. In conclusion, results suggest that smoking is associated with three early-indicators of cerebrovascular burden (WM-fractional anisotropy, WM abnormal volume, and CBF) across the brain and that it may be differentially related to different regional cerebrovascular indicators.

Download Full-text

Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00319.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. L59-L64 ◽

Cited By ~ 6

Author(s):

Haoxiao Zuo ◽

Alen Faiz ◽

Maarten van den Berge ◽

Senani N. H. Rathnayake Mudiyanselage ◽

Theo Borghuis ◽

...

Keyword(s):

Cigarette Smoke ◽

Cyclic Nucleotides ◽

Complex Mixture ◽

Inflammatory Cells ◽

Pde4 Inhibitor ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Pde Inhibition ◽

Never Smokers

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.

Download Full-text

Effects of cigarette smoke on pulmonary endothelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00373.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. L743-L756 ◽

Cited By ~ 15

Author(s):

Qing Lu ◽

Eric Gottlieb ◽

Sharon Rounds

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cigarette Smoking ◽

Cigarette Smoke ◽

The United States ◽

Smoke Exposure ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

Cell Functions ◽

Pulmonary Endothelial Cells

Cigarette smoking is the leading cause of preventable disease and death in the United States. Cardiovascular comorbidities associated with both active and secondhand cigarette smoking indicate the vascular toxicity of smoke exposure. Growing evidence supports the injurious effect of cigarette smoke on pulmonary endothelial cells and the roles of endothelial cell injury in development of acute respiratory distress syndrome (ARDS), emphysema, and pulmonary hypertension. This review summarizes results from studies of humans, preclinical animal models, and cultured endothelial cells that document toxicities of cigarette smoke exposure on pulmonary endothelial cell functions, including barrier dysfunction, endothelial activation and inflammation, apoptosis, and vasoactive mediator production. The discussion is focused on effects of cigarette smoke-induced endothelial injury in the development of ARDS, emphysema, and vascular remodeling in chronic obstructive pulmonary disease.

Download Full-text

The role of oxidative stress in lung injury induced by cigarette smoke

Biologia ◽

10.2478/s11756-006-0135-4 ◽

2006 ◽

Vol 61 (6) ◽

Cited By ~ 5

Author(s):

Zuzana Kluchová ◽

Ružena Tkáčová

Keyword(s):

Oxidative Stress ◽

Cigarette Smoking ◽

Lung Injury ◽

Cigarette Smoke ◽

Current Knowledge ◽

Inflammatory Cells ◽

Systemic Circulation ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Markers Of Oxidative Stress

AbstractOxidative stress is a damaging process resulting from an imbalance between excessive generation of oxidant compounds and insufficient antioxidant defence mechanisms. Oxidative stress plays a crucial role in the initiation and progression of cigarette smoke-induced lung injury, deterioration in lung functions, and development of chronic obstructive pulmonary disease (COPD). In smokers and in patients with COPD, the increased oxidant burden derives from cigarette smoke per se, and from activated inflammatory cells releasing enhanced amounts of reactive oxygen and nitrogen species (ROS, RNS, respectively). Although mild oxidative stress resulting from cigarette smoking leads to the upregulation of the antioxidative enzymes synthesis in the lungs, high levels of ROS and RNS observed in patients with COPD overwhelm the antioxidant enzymes capacities, resulting in oxidant-mediated lung injury and cell death. In addition, depletion of antioxidative systems in the systemic circulation was consistently observed in such patients. The imbalance between the generation of ROS/RNS and antioxidant capacities — the state of “oxidative stress” — is one of the major pathophysiologic hallmarks in the development of COPD. Detrimental effects of oxidative stress include impairment of membrane functions, inactivation of membrane-bound receptors and enzymes, and increased tissue permeability. In addition, oxidative stress aggravates the inflammatory processes in the lungs, and contributes to the worsening of the protease-antiprotease imbalance. Several markers of oxidative stress, such as increases in lipid peroxidation products and reductions in glutathione peroxidase activity, have been shown to be related to the reductions in pulmonary functions. In the present article we review the current knowledge about the vicious cycle of cigarette smoking, oxidative stress, and inflammation in the pathogenesis of COPD.

Download Full-text

Smoking tends to decrease glutathione and increase malondialdehyde levels in medical students

Zinc supplementation improves heme biosynthesis in rats exposed to lead ◽

10.18051/univmed.2016.v35.89-95 ◽

2016 ◽

Vol 35 (2) ◽

pp. 89 ◽

Cited By ~ 1

Author(s):

Safyudin Safyudin ◽

Subandrate Subandrate

Keyword(s):

Medical Students ◽

Cigarette Smoke ◽

The Body ◽

Smoking History ◽

Chronic Obstructive ◽

Toxic Substances ◽

Cross Sectional ◽

Obstructive Pulmonary Disease ◽

Significant Difference ◽

Endogenous Antioxidant

Background Smoking is the act of introducing toxic substances into the body. Cigarette smoke contains chemicals that may cause several disorders, including cardiovascular disease, cancer, and chronic obstructive pulmonary disease. Toxic substances in cigarette smoke have the potential to increase free radicals, malondialdehyde (MDA) levels and to decrease endogenous antioxidant (glutathione/GSH) levels. This study aims to determine the relationship of smoking with plasma GSH and MDA levels in medical students. Methods This study was analytical observational with cross-sectional approach. The study was conducted from April to December 2015. The subjects in this study were medical students, consisting of 20 smokers and 20 nonsmokers. Plasma GSH and MDA levels were determined biochemically using Sigma GSH Assay Kit and Sigma MDA Assay Kit. Data was analyzed using the independent t test. Results The results showed that there was no significant difference between mean GSH in smokers (1.74 ± 0.91 mmol/L) and nonsmokers (2.42 ± 1.19 µmol/L) (p=0.441). Mean smokers MDA level of 2.06 ± 1.39 nmol/mL was not significantly different compared with mean nonsmokers MDA level (1.32 ± 0.90 nmol/mL) (p=0.092). Conclusions Smoking tends to decrease plasma GSH levels and increase plasma MDA levels in medical students. Smoking history could be evidence of oxidative stress and an impaired oxidant defense system. In particular, young smokers should quit promptly before health problems arise, so as to have the optimal benefits of cessation.

Download Full-text