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Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice.

ABSTRACT: Cigarette smoke is well recognized to cause injury to the airways and the alveolar walls over time. This injury usually requires many years of exposure, suggesting that the lungs may rapidly develop responses that initially protect it from this repetitive injury. Our studies tested the hypotheses that smoke induces an inflammatory response and changes in mRNA profiles that are dependent on sex and the health status of the lung, and that the response of the lungs to smoke differs after 1 day compared to 5 days of exposure. Male and female wildtype (WT) and Scnn1b-transgenic (?ENaC) mice, which have chronic bronchitis and emphysematous changes due to dehydrated mucus, were exposed to cigarette smoke or sham air conditions for 1 or 5 days. The inflammatory response and gene expression profiles were analyzed in lung tissue. Overall, the inflammatory response to cigarette smoke was mild, and changes in mediators were more numerous after 1 than 5 days. ?ENaC mice had more airspace leukocytes than WT mice, and smoke exposure resulted in additional significant alterations. Many genes and gene sets responded similarly at 1 and 5 days: genes involved in oxidative stress responses were upregulated while immune response genes were downregulated. However, certain genes and biological processes were regulated differently after 1 compared to 5 days. Extracellular matrix biology genes and gene sets were upregulated after 1 day but downregulated by 5 days of smoke compared to sham exposure. There was no difference in the transcriptional response to smoke between WT and ?ENaC mice or between male and female mice at either 1 or 5 days. Taken together, these studies suggest that the lungs rapidly alter gene expression after only one exposure to cigarette smoke, with few additional changes after four additional days of repeated exposure. These changes may contribute to preventing lung damage.

SUBMITTER: Engle ML

PROVIDER: S-EPMC6395068 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice.

Engle Michelle L ML Monk Justine N JN Jania Corey M CM Martin Jessica R JR Gomez John C JC Dang Hong H Parker Joel S JS Doerschuk Claire M CM

PloS one 20190228 2

Cigarette smoke is well recognized to cause injury to the airways and the alveolar walls over time. This injury usually requires many years of exposure, suggesting that the lungs may rapidly develop responses that initially protect it from this repetitive injury. Our studies tested the hypotheses that smoke induces an inflammatory response and changes in mRNA profiles that are dependent on sex and the health status of the lung, and that the response of the lungs to smoke differs after 1 day comp ...[more]

PMID: 30818335

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Project description:BACKGROUND:Lung aging is characterized by a number of structural alterations including fibrosis, chronic inflammation and the alteration of inflammatory cell composition. Chronic exposure to cigarette smoke (CS) is known to induce similar alterations and may contribute to premature lung aging. Additionally, aging and CS exposure are associated with transcriptional alterations in the lung. The current work aims to explore the interaction between age- and CS- associated transcriptomic perturbations and develop a transcriptomic clock able to predict the biological age and the impact of external factors on lung aging. RESULTS:Our investigations revealed a substantial overlap between transcriptomic response to CS exposure and age-related transcriptomic alterations in the murine lung. Of particular interest is the strong upregulation of immunoglobulin genes with increased age and in response to CS exposure, indicating an important implication of B-cells in lung inflammation associated with aging and smoking. Furthermore, we used a machine learning approach based on Lasso regression to build a transcriptomic age model that can accurately predict chronological age in untreated mice and the deviations associated with certain exposures. Interestingly, CS-exposed-mice were predicted to be prematurely aged in contrast to mice exposed to fresh air or to heated tobacco products (HTPs). The accelerated aging rate associated with CS was reversed upon smoking cessation or switching to HTPs. Additionally, our model was able to predict premature aging associated with thoracic irradiation from an independent public dataset. CONCLUSIONS:Aging and CS exposure share common transcriptional alteration patterns in the murine lung. The massive upregulation of B-cell restricted genes during these processes shed light on the contribution of cell composition and particularly immune cells to the measured transcriptomic signal. Through machine learning approach, we show that gene expression changes can be used to accurately monitor the biological age and the modulations associated with certain exposures. Our findings also suggest that the premature lung aging is reversible upon the reduction of harmful exposures.

Project description:IntroductionCigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice.MethodsAdult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA.ResultsIn CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability.ConclusionsThese results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury.ImplicationsOur results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury.

Project description:Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine.

Dataset Information

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice.

Publications

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice.

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