Impact Of Cigarette Smoke Exposure Research Articles

Brain Glucose Metabolism as a Readout of the Central Nervous System Impact of Cigarette Smoke Exposure and Withdrawal and the Effects of NFL-101, as an Immune-Based Drug Candidate for Smoking Cessation Therapy.

Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [18F]fluoro-deoxy-glucose ([18F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily). Compared with control animals, the relative uptake of [18F]FDG in CSE mice was decreased in the thalamus and brain stem (p < 0.001, n = 14 per group) and increased in the hippocampus, cortex, cerebellum, and olfactory bulb (p < 0.001). NFL-101 induced a humoral immune response (specific IgGs) in mice and activated human natural-killer lymphocytes in vitro. In CSE mice, but not in control mice, single-dose NFL-101 significantly increased [18F]FDG uptake in the thalamus (p < 0.01), thus restoring normal brain glucose metabolism after 2-day withdrawal in this nicotinic receptor-rich region. In tobacco research, [18F]FDG PET imaging provides a quantitative method to evaluate changes in the brain function associated with the withdrawal phase. This method also showed the CNS effects of NFL-101, with translational perspectives for future clinical evaluation in smokers.

Cigarette smoking exposure disrupts the regenerative potential of dental pulp stem cells.

Smoking is known to alter the regenerative and immunomodulatory properties of many types of mesenchymal stem cells (MSCs). This study investigates the impact of cigarette smoke exposure on the regenerative potential of dental pulp stem cells (DPSCs). DPSCs were treated with various doses of cigarette smoke condensate (CSC) or nicotine. Cell proliferation and survival were evaluated by a water-soluble tetrazolium salt (WST-1) and a survival assay. DPSC migration, cytokine expression, mutagenesis, and the signaling pathway were also measured during CSC and nicotine treatment. Low concentrations of CSC and nicotine did not impair cell proliferation, but higher concentrations reduced cell proliferation. CSC and nicotine could impede DPSC survival and migration in a dose-dependent manner. In addition, the cytokine secretion expression profile was altered with CSC or nicotine treatments. In particular, secretion of IL-6, TNF-α, and IL-10 significantly increased, while TGF-β1 levels showed different patterns after exposure to CSC or nicotine, as shown by ELISA and quantitative PCR. Nicotine treatment increased AKT (also known as protein kinase B) and extracellular signal-regulated kinase (ERK) phosphorylation. Finally, CSC induced higher levels of mutagenicity than nicotine, as shown by the Ames test. These findings suggest that cigarette smoke exposure alters the regenerative abilities of DPSCs in various ways. Future studies are warranted to further characterize the underlying molecular mechanisms of smoking-mediated damage to DPSCs, which will guide the personalized stem cell treatment plan for smoking patients.

Understanding cigarette smoking among mothers with opioid use disorder

BackgroundCigarette smoking is highly prevalent among mothers with opioid use disorder (OUD). Organizations such as the American College of Obstetrics and Gynecology recommend cessation of cigarettes during the pre- and postnatal periods. Factors that inform decisions to continue or stop smoking cigarettes among pregnant and postpartum mothers with OUD are unclear. AimsThis study aimed to understand (1) the lived experience of mothers with OUD regarding cigarette smoking and (2) barriers and facilitators to reduction of cigarette smoking during the pre- and postnatal periods. MethodsGuided by the Theory of Planned Behavior (TPB) framework, we completed semi-structured, in-depth interviews with mothers with OUD with infants 2–7 months of age. We used an iterative approach to analysis by conducting interviews and developing and revising codes and themes until we reached thematic saturation. ResultsFifteen of 23 mothers reported smoking cigarettes prenatally and postnatally, 6 of 23 smoked cigarettes during the prenatal period only, and 2 mothers were non-smokers. We found that mothers: 1) believed that smoke exposure had negative health consequences and may exacerbate withdrawal symptoms for their infants; 2) implemented risk mitigation practices, which were dictated both by themselves and by outside rules, to reduce the harmful effects of smoke around infants; 3) were motivated to quit or cut-down on smoking because of the desire to optimize the health and well-being of their infants; 4) continued to smoke because they felt that the stress related to caregiving and their own recovery were a higher priority than quitting smoking; and 5) were influenced by exposure to smokers with whom they lived, as well as by the varied advice of medical providers, family, and friends. ConclusionWhile mothers with OUD acknowledged the negative health impact of cigarette smoke exposure to their infants, many experienced stressors related to recovery and caregiving unique to those with OUD that impacted their cigarette smoking behaviors.

Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models.

ABSTRACTExposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely understood. Undifferentiated or differentiated primary bronchial epithelial cells were acutely/chronically exposed to whole CS (WCS) or CS extract (CSE) in submerged or air–liquid interface conditions. Abundance of key regulators controlling mitochondrial biogenesis, mitophagy and mitochondrial dynamics was assessed. Acute exposure to WCS or CSE increased the abundance of components of autophagy and receptor-mediated mitophagy in all models. Although mitochondrial content and dynamics appeared to be unaltered in response to CS, changes in both the molecular control of mitochondrial biogenesis and a shift toward an increased glycolytic metabolism were observed in particular in differentiated cultures. These alterations persisted, at least in part, after chronic exposure to WCS during differentiation and upon subsequent discontinuation of WCS exposure. In conclusion, smoke exposure alters the regulation of mitochondrial metabolism in airway epithelial cells, but observed alterations may differ between various culture models used. This article has an associated First Person interview with the joint first authors of the paper.

Cigarette Smoke or Cigarette Condensate Exposure Enhances Growth of FLT3-ITD AML Models and Alters DNA Methylation and Leukemic Gene Expression

Cigarette Smoke or Cigarette Condensate Exposure Enhances Growth of FLT3-ITD AML Models and Alters DNA Methylation and Leukemic Gene Expression

Abstract A06: Impact of cigarette smoke exposure on acute myeloid leukemia progression

Abstract Cigarette smoke is known to cause lung cancer but is also associated with increased incidence of leukemia. Acute myeloid leukemia (AML) is the most lethal form of leukemia, and patients who are or were smokers have increased risk of developing AML and have worse prognosis. There is also an increased incidence of AML in children whose parents smoked either during or after the pregnancy. It is currently unknown how cigarette smoke exposure (CSE) may be impacting leukemic progression or treatment efficacy in AML. Cigarette smoking increases levels of reactive oxygen species (ROS) in the tissue of smokers, including peripheral blood samples. Oxidative stress can alter epigenetic signaling, including DNA methylation. Oxidation of methylated DNA and oxidative lesions on DNA can alter normal DNA methylation patterns. Smokers have altered DNA methylation that can be retained decades after the cessation of the habit, and these changes can be found in the blood cells of smokers. Cigarette smoke condensate (CSC) treatment has also been seen to epigenetically prime nontransformed human bronchial cells for malignant transformation. These occurrences have been seen in the context of lung cancer and lung damage, but studies into other tissue damage have largely been overlooked. Thus, we hypothesize that CSE impacts leukemic progression and treatment in AML through these mechanisms. We have developed a model to study the impact of CSE on AML in mice. NOD-SCID mice are smoke exposed for two weeks prior to being engrafted with luciferase-labeled human AML cells. The CSE is performed in the SCIREQ Cigarette Smoking Robot, with 3R4F research cigarettes 5 days/week. We include experimental arms of smoking cessation (who stop once evidence of leukemic engraftment is detected) and continued smoking, to model patients who either stop or continue smoking upon diagnosis of AML. Leukemic burden is quantified through bioluminescent imaging throughout the experiment. From these models, we have observed that two weeks of CSE is sufficient to significantly increase (p-value&amp;lt;0.0001) early leukemic burden as compared to non-smoke exposed mice, in FLT3-ITD AML-bearing mice. Spleen samples revealed trends of increased levels of superoxides in the CSE mice. Currently, immunohistochemistry is being performed on collected organs to detect oxidative stress markers. Additionally, mouse spleen DNA underwent reduced representative bisulfide sequencing; the levels of DNA methylation in the mouse host cells and in the leukemia are compared between our CSE groups. This is the first description of CSE promoting leukemia growth in mouse model, which will enable the study of mechanistic aspects. This may help define if unique treatment strategies are needed for these patients. Citation Format: Yue Lu, Marcos Estecio, Marina Konopleva, Elias Jabbour, Joya Chandra, Mary Figueroa. Impact of cigarette smoke exposure on acute myeloid leukemia progression [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A06.

Effects of Cigarette Smoke on the Nasal Respiratory and Olfactory Mucosa in Allergic Rhinitis Mice.

ObjectiveCigarette smoke (CS) exposure reportedly enhances allergic airway inflammation. However, some studies have shown an association between current cigarette smoke exposure and a low risk for allergic rhinitis. Thus, the impact of CS exposure on allergic rhinitis remains poorly understood. The purpose of this study was to investigate the effects of CS on the respiratory mucosa (RM) and the olfactory epithelium (OE) of mice with allergic rhinitis, as the effects may differ depending on the nasal histological compartments.MethodsEight-week-old male BALB/c mice were used for this study. We developed a mouse model of smoking by intranasally administering 10 doses of a CS solution (CSS), and a mouse model of allergic rhinitis by sensitization with intraperitoneal ovalbumin (OVA) injection and intranasal challenge with OVA. We examined the effects of CS on the nasal RM and OE in mice with or without allergic rhinitis using histological, serum, and genetic analyses. First, we examine whether CSS exposure induces allergic responses and then, examined allergic responses in the OVA-sensitized allergic rhinitis mice with or without CSS exposure.ResultsShort-term CSS administration intensified allergic responses including increased infiltration of eosinophils and inflammatory cells and upregulation of interleukin-5 expression in the nasal RM of OVA-immunized mice, although only CSS induced neither allergic responses nor impairment of the RM and OE. Notably, repetitive OVA-immunization partially impaired the OE in the upper-lateral area, but CSS administration did not reinforce this impairment in OVA-induced allergic mice.ConclusionShort-term CSS exposure strengthened allergic responses in the nasal RM and did not change the structure of the OE. These results suggest that patients with allergic rhinitis could experience exacerbation of allergic symptoms after CS exposure.

Role of KRAS in regulating normal human airway basal cell differentiation

BackgroundKRAS is a GTPase that activates pathways involved in cell growth, differentiation and survival. In normal cells, KRAS-activity is tightly controlled, but with specific mutations, the KRAS protein is persistently activated, giving cells a growth advantage resulting in cancer. While a great deal of attention has been focused on the role of mutated KRAS as a common driver mutation for lung adenocarcinoma, little is known about the role of KRAS in regulating normal human airway differentiation.MethodsTo assess the role of KRAS signaling in regulating differentiation of the human airway epithelium, primary human airway basal stem/progenitor cells (BC) from nonsmokers were cultured on air-liquid interface (ALI) cultures to mimic the airway epithelium in vitro. Modulation of KRAS signaling was achieved using siRNA-mediated knockdown of KRAS or lentivirus-mediated over-expression of wild-type KRAS or the constitutively active G12 V mutant. The impact on differentiation was quantified using TaqMan quantitative PCR, immunofluorescent and immunohistochemical staining analysis for cell type specific markers. Finally, the impact of cigarette smoke exposure on KRAS and RAS protein family activity in the airway epithelium was assessed in vitro and in vivo.ResultssiRNA-mediated knockdown of KRAS decreased differentiation of BC into secretory and ciliated cells with a corresponding shift toward squamous cell differentiation. Conversely, activation of KRAS signaling via lentivirus mediated over-expression of the constitutively active G12 V KRAS mutant had the opposite effect, resulting in increased secretory and ciliated cell differentiation and decreased squamous cell differentiation. Exposure of BC to cigarette smoke extract increased KRAS and RAS protein family activation in vitro. Consistent with these observations, airway epithelium brushed from healthy smokers had elevated RAS activation compared to nonsmokers.ConclusionsTogether, these data suggest that KRAS-dependent signaling plays an important role in regulating the balance of secretory, ciliated and squamous cell differentiation of the human airway epithelium and that cigarette smoking-induced airway epithelial remodeling is mediated in part by abnormal activation of KRAS-dependent signaling mechanisms.

A lower impact of an acute exposure to electronic cigarette aerosols than to cigarette smoke in human organotypic buccal and small airway cultures was demonstrated using systems toxicology assessment

In the context of tobacco harm-reduction strategy, the potential reduced impact of electronic cigarette (EC) exposure should be evaluated relative to the impact of cigarette smoke exposure. We conducted a series of in vitro studies to compare the biological impact of an acute exposure to aerosols of “test mix” (flavors, nicotine, and humectants), “base” (nicotine and humectants), and “carrier” (humectants) formulations using MarkTen® EC devices with the impact of exposure to smoke of 3R4F reference cigarettes, at a matching puff number, using human organotypic air–liquid interface buccal and small airway cultures. We measured the concentrations of nicotine and carbonyls deposited in the exposure chamber after each exposure experiment. The deposited carbonyl concentrations were used as representative measures to assess the reduced exposure to potentially toxic volatile substances. We followed a systems toxicology approach whereby functional biological endpoints, such as histopathology and ciliary beating frequency, were complemented by multiplex and omics assays to measure secreted inflammatory proteins and whole-genome transcriptomes, respectively. Among the endpoints analyzed, the only parameters that showed a significant response to EC exposure were secretion of proteins and whole-genome transcriptomes. Based on the multiplex and omics analyzes, the cellular responses to EC aerosol exposure were tissue type-specific; however, those alterations were much smaller than those following cigarette smoke exposure, even when the EC aerosol exposure under the testing conditions resulted in a deposited nicotine concentration approximately 200 times that in saliva of EC users.

The impact of cigarette smoke exposure, COPD, or asthma status on ABC transporter gene expression in human airway epithelial cells

ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. We used a bioinformatic approach complemented with in vitro experimental methods for validation of the 48 known human ABC transporters in airway epithelial cells using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma, with validation performed in Calu-3 airway epithelial cells. Gene expression data demonstrate that ABC transporters are variably expressed in epithelial cells from different airway generations, regulated by cigarette smoke exposure (ABCA13, ABCB6, ABCC1, and ABCC3), and differentially expressed in individuals with COPD and asthma (ABCA13, ABCC1, ABCC2, ABCC9). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate select observed in situ changes. Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.

Modelling the asthma phenotype: impact of cigarette smoke exposure

BackgroundAsthmatics that are exposed to inhaled pollutants such as cigarette smoke (CS) have increased symptom severity. Approximately 25% of adult asthmatics are thought to be active smokers and many sufferers, especially in the third world, are exposed to high levels of inhaled pollutants. The mechanism by which CS or other airborne pollutants alter the disease phenotype and the effectiveness of treatment in asthma is not known. The aim of this study was to determine the impact of CS exposure on the phenotype and treatment sensitivity of rodent models of allergic asthma.MethodsModels of allergic asthma were configured that mimicked aspects of the asthma phenotype and the effect of CS exposure investigated. In some experiments, treatment with gold standard asthma therapies was investigated and end-points such as airway cellular burden, late asthmatic response (LAR) and airway hyper-Reactivity (AHR) assessed.ResultsCS co-exposure caused an increase in the LAR but interestingly attenuated the AHR. The effectiveness of LABA, LAMA and glucocorticoid treatment on LAR appeared to be retained in the CS-exposed model system. The eosinophilia or lymphocyte burden was not altered by CS co-exposure, nor did CS appear to alter the effectiveness of glucocorticoid treatment. Steroids, however failed to reduce the neutrophilic inflammation in sensitized mice exposed to CS.ConclusionsThese model data have certain parallels with clinical findings in asthmatics, where CS exposure did not impact the anti-inflammatory efficacy of steroids but attenuated AHR and enhanced symptoms such as the bronchospasm associated with the LAR. These model systems may be utilised to investigate how CS and other airborne pollutants impact the asthma phenotype; providing the opportunity to identify novel targets.

Cigarette smoke exposure promotes differentiation of CD4+ T cells toward Th17 cells by CD40-CD40L costimulatory pathway in mice.

PurposeThis study aimed to investigate the impact of cigarette smoke exposure upon CD40–CD40L ligation between bone marrow-derived dendritic cells (BMDCs)and CD4+T cells, and to examine the effects of cigarette smoke exposure upon differentiation of CD4+T cells toward Th17 cells through blockade of CD40-CD40L pathway in mice.MethodsThe study was processed in vivo and in vitro. In vivo, Th17 cells, CD40, interleukin (IL)-17A, and IL-27 in the lung tissues were quantified and compared between mice with and without cigarette smoke exposure. In vitro, Th17 cells, IL-17A, and IL-27 yielded by multiple cell cultivations in which BMDCs from mice with or without cigarette smoke exposure were fostered with CD4+ T cells from healthy mice spleens in the presence of antagonistic CD40 antibody and/or cigarette smoke extract (CSE) were quantified and compared. The flow cytometry was used to detect expressions of Th17 cells and CD40, and the liquid chip was used to detect levels of IL-17A and IL-27.ResultsBoth in vivo exposed to cigarette smoke and in vitro to CSE, CD40 expressions noticeably escalated on the surfaces of BMDCs. The presence of Th17 cells, IL-17A, and IL-27 in the lung tissues prominently increased in mice exposed to cigarette smoke. The in vitro culture of CD4+ T cells and BMDCs significantly enhanced the differentiation of CD4+ T cells toward Th17 cells and secretions of IL-17A and IL-27 in the case that BMDCs were produced from mice exposed to cigarette smoke or the culture occurred in the presence of CSE. Usage of antagonistic CD40 antibody evidently reduced the number of Th17 cells, IL-17A, and IL-27 that increased due to cigarette smoke exposure.ConclusionThe CD40–CD40L ligation is associated with the quantities of Th17 cells and relevant cytokines in the context of cigarette smoke exposure. Reducing the number of Th17 cells via the usage of antagonistic CD40 antibody can be an inspiration for pursuing a novel therapeutic target for immune inflammation in COPD.

An assay to characterize the impact of cigarette smoke exposure on mucociliary clearance in-vitro

An assay to characterize the impact of cigarette smoke exposure on mucociliary clearance in-vitro

Cigarette smoking significantly alters sperm DNA methylation patterns.

Numerous health consequences of tobacco smoke exposure have been characterized, and the effects of smoking on traditional measures of male fertility are well described. However, a growing body of data indicates that pre-conception paternal smoking also confers increased risk for a number of morbidities on offspring. The mechanism for this increased risk has not been elucidated, but it is likely mediated, at least in part, through epigenetic modifications transmitted through spermatozoa. In this study, we investigated the impact of cigarette smoke exposure on sperm DNA methylation patterns in 78 men who smoke and 78 never-smokers using the Infinium Human Methylation 450 beadchip. We investigated two models of DNA methylation alterations: (i) consistently altered methylation at specific CpGs or within specific genomic regions and (ii) stochastic DNA methylation alterations manifest as increased variability in genome-wide methylation patterns in men who smoke. We identified 141 significantly differentially methylated CpGs associated with smoking. In addition, we identified a trend toward increased variance in methylation patterns genome-wide in sperm DNA from men who smoke compared with never-smokers. These findings of widespread DNA methylation alterations are consistent with the broad range of offspring heath disparities associated with pre-conception paternal smoke exposure and warrant further investigation to identify the specific mechanism by which sperm DNA methylation perturbation confers risk to offspring health and whether these changes can be transmitted to offspring and transgenerationally.

Abstract 2691: Cigarette smoke induced upregulation of endothelin axis in the initiation of pancreatic cancer

Abstract Background: Cigarette smoke is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Smoke induced inflammation accelerates the progression of PDAC in presence of constitutively active K-Ras mutation. Endothelin (ET) axis comprising of endothelin converting enzymes (ECE-1, ECE-2, and ECE-3), endothelin isoforms (ET-1, ET-2 and ET-3) and two receptors A (ETAR) and B (ETBR), is linked to pathobiology of pancreatitis and its components exhibit aberrant overexpression in PDAC. However, the expression of ET-axis in the oncogene-associated early Pancreatic Intraepithelial neoplastic (PanINs) lesions following exposure to cigarette smoke is unknown. We hypothesize that smoke induced alterations in the ET axis facilitate acinar to ductal metaplasia (ADM) in presence of oncogenic K-Ras. Thus, we characterized the impact of cigarette smoke exposure on ET axis components in the pancreas of mice harboring mutant K-Ras. Methods: Expression of ECE-1, ET-1, ETAR and ETBR was analyzed by IHC and RT-PCR first in the murine model of preneoplastic lesions [KC model: (Pdx1-Cre, KrasG12D)). To determine the changes in ET axis after smoke exposure, wild type (WT) and KC mutant mice were exposed to cigarette smoke for 20 weeks and expression was analyzed in the pancreas. The impact of smoking on ET-axis was also studied on murine acinar and tumor cell lines derived from KC mice (UN-KC6141) and KPC (Pdx1-Cre, p53 (R172H) KrasG12D) mice (UN-KPC-961) by western blot and RT-PCR analysis. Results: In contrast to the normal ducts, the expression of ECE-1, ET-1, ETAR and ETBR was upregulated in the early PaNIN lesions (20-30 weeks). In the advanced lesions (50 weeks), significant overexpression of all four molecules was noticeable in the tumor cells and stromal compartment. Smoke exposure resulted in significant increase in the transcripts of ET-1, ETAR and ETBR (p values = 0.04, 0.03 and 0.01 respectively) in the KC mice while the increase in WT mice was not significant. The changes in the expression were also corroborated by tissue IHC. Expression of ET axis components was predominantly seen in the islet cells in WT mice, while low immunoreactivity was observed in the acinar compartment. Smoke exposure of KC mice resulted in accelerated progression of PanIN lesions along with concomitant increase in the expression of ET axis components both in the ductal and stromal cells. In vitro exposure of cigarette smoke extract (CSE) to UN-KC6141 and UN-KPC-961 cells for 24 hours elicited a dose dependent upregulation of ECE 1 and ET-1. Conclusions: In presence of mutated KrasG12D, smoking-mediated inflammatory insult promotes PanIN progression and tumorigenesis. The sustained increase and activation of ET axis with increasing dysplasia in the ductal compartment during this progression in KC mice and its further upregulation following smoke exposure suggests its possible role in promoting inflammation-associated pancreatic tumor progression. Citation Format: Suprit Gupta, Satyanarayana Rachagani, Sushil Kumar, Surinder Kumar Batra, Maneesh Jain. Cigarette smoke induced upregulation of endothelin axis in the initiation of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2691. doi:10.1158/1538-7445.AM2017-2691

Smoking fruit flies – Impact of cigarette smoke exposure on the airway epithelium of Drosophila melanogaster

Smoking fruit flies – Impact of cigarette smoke exposure on the airway epithelium of Drosophila melanogaster

Impact of cigarette smoke exposure on the expression of cardiac hypertrophic genes, cytochrome P450 enzymes, and oxidative stress markers in rats

Various experimental and clinical studies strongly support a cigarette smoke-heart disease association and suggest possible mechanisms, unfortunately, the involvement of genetic modulations remain unexplored. Thus, the main aim of the current study was to evaluate the effects of sub-chronic cigarette smoke exposure on the mRNA expression of cardiac hypertrophy genes, cytochrome P450 (CYP) enzymes, and the oxidative stress markers in heart rats. For this purpose, Wistar albino rats were exposed to increasing doses of passive cigarette smoke 2, 4, 8, and 24 cigarettes per day for 7 consecutive days. The mRNA expression of fifteen cardiac genes was determined using real-time polymerase chain reaction. Our results showed that the levels of hypertrophic genes; atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain were significantly induced, whereas the anti-hypertrophic gene α-myosin heavy chain was dramatically inhibited, in heart tissues of passive-smoke-exposed groups compared with normal-control groups. This was accompanied with a significant induction of CYP enzymes; CYP1A1, CYP2C11, CYP2E1, and CYP3A2, and the expression of oxidative stress genes, heme oxygenase 1, catalase, cyclooxygenase, and glutathione S-Transferase. The ability of cigarette smoke to induce cardiac hypertrophic genes, CYPs enzymes, and oxidative stress, collectively explore the molecular mechanism of cigarette smoke-induced cardiac diseases and brings further investigative attention to the public health issue of the injurious effects of chronic passive smoke exposure. In conclusion, sub-chronic environmental tobacco smoke exposure increases the incidence of cardiovascular diseases through modulation of cardiac genes.

A computable cellular stress network model for non-diseased pulmonary and cardiovascular tissue

BackgroundHumans and other organisms are equipped with a set of responses that can prevent damage from exposure to a multitude of endogenous and environmental stressors. If these stress responses are overwhelmed, this can result in pathogenesis of diseases, which is reflected by an increased development of, e.g., pulmonary and cardiac diseases in humans exposed to chronic levels of environmental stress, including inhaled cigarette smoke (CS). Systems biology data sets (e.g., transcriptomics, phosphoproteomics, metabolomics) could enable comprehensive investigation of the biological impact of these stressors. However, detailed mechanistic networks are needed to determine which specific pathways are activated in response to different stressors and to drive the qualitative and eventually quantitative assessment of these data. A current limiting step in this process is the availability of detailed mechanistic networks that can be used as an analytical substrate.ResultsWe have built a detailed network model that captures the biology underlying the physiological cellular response to endogenous and exogenous stressors in non-diseased mammalian pulmonary and cardiovascular cells. The contents of the network model reflect several diverse areas of signaling, including oxidative stress, hypoxia, shear stress, endoplasmic reticulum stress, and xenobiotic stress, that are elicited in response to common pulmonary and cardiovascular stressors. We then tested the ability of the network model to identify the mechanisms that are activated in response to CS, a broad inducer of cellular stress. Using transcriptomic data from the lungs of mice exposed to CS, the network model identified a robust increase in the oxidative stress response, largely mediated by the anti-oxidant NRF2 pathways, consistent with previous reports on the impact of CS exposure in the mammalian lung.ConclusionsThe results presented here describe the construction of a cellular stress network model and its application towards the analysis of environmental stress using transcriptomic data. The proof-of-principle analysis described here, coupled with the future development of additional network models covering distinct areas of biology, will help to further clarify the integrated biological responses elicited by complex environmental stressors such as CS, in pulmonary and cardiovascular cells.

Impact of cigarette smoke exposure on host-bacterial pathogen interactions

The human respiratory tract of individuals with normal lung function maintains a fine-tuned balance, being asymptomatically colonised by the normal microbiota in the upper airways and sterile in the lower tract. This equilibrium may be disrupted by the exposure to insults such as cigarette smoke. In the respiratory tract, the complex and noxious nature of inhaled cigarette smoke alters host-microorganism interaction dynamics at all anatomical levels, causing infections in many cases. Moreover, continuous exposure to cigarette smoke itself causes deleterious effects on the host that can trigger the development of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. COPD is an irreversible airflow obstruction associated with emphysema, fibrosis, mucus hypersecretion and persistent colonisation of the lower airways by opportunistic pathogens. COPD patients keep a stable (without exacerbation) but progressively worsening condition and suffer periodic exacerbations caused, in most cases, by infections. Although smoking and smoking-associated diseases are associated with a high risk of infection, most therapies aim to reduce inflammatory parameters, but do not necessarily take into account the presence of persistent colonisers. The effect of cigarette smoke on host-pathogen interaction dynamics in the respiratory tract, together with current and novel therapies, is discussed.

Pathophysiological Impact of Cigarette Smoke Exposure on the Cerebrovascular System with a Focus on the Blood-brain Barrier: Expanding the Awareness of Smoking Toxicity in an Underappreciated Area

Recent evidence has indicated that active and passive cigarette smoking are associated, in a dose-dependent manner, with dysfunction of normal endothelial physiology. Tobacco smoke (TS) may predispose individuals to atherogenic and thrombotic problems, significantly increasing the risk for ischemic manifestations such as acute coronary syndrome and stroke. Despite the strong evidence for an association between smoking and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has only been marginally addressed. This is a major problem given that the BBB is crucial in the maintenance of brain homeostasis. Recent data have also shown that chronic smokers have a higher incidence of small vessel ischemic disease (SVID), a pathological condition characterized by leaky brain microvessels and loss of BBB integrity. In the brain TS increases the risk of silent cerebral infarction (SCI) and stroke owing to the pro-coagulant and atherogenic effects of smoking. In this article we provide a detailed review and analysis of current knowledge of the pathophysiology of tobacco smoke toxicity at the cerebrovascular levels. We also discuss the potential toxicity of recently marketed “potential-reduced exposure products”.