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

Michelle L Engle,Corey M Jania,Justine N Monk,Joel S Parker,Claire M Doerschuk,Jessica R Martin,John C Gomez,Hong Dang,Ali Önder Yildirim

doi:10.1371/journal.pone.0212866

Michelle L Engle, Corey M Jania + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0212866

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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 (βENaC) 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. βENaC 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 βENaC 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.

Highlights

Cigarette smoke is a leading health hazard and causes an enormous impact on lung health
Leukocytes were quantified in the bronchoalveolar lavage (BAL) fluid collected from male and female WT and βENaC mice after 1-day (Fig 1) or 5-day (Fig 2) exposure to smoke
Our study tested the hypothesis that the pulmonary response to cigarette smoke, as measured by the immune response and the expression of exposure-response genes is rapid and changes over the short duration of 5 days

Summary

Introduction

Cigarette smoke is a leading health hazard and causes an enormous impact on lung health. The response of the lungs to the first exposure of cigarette smoke and how this response changes following subsequent exposures is important for understanding tobacco-induced lung injury and is nearly impossible to study in humans. The effect of a single exposure to cigarette smoke on gene expression in the lungs has not been evaluated. Most interesting are questions about changes that occur in response to a single dose of cigarette smoke compared to changes resulting from consecutive repeated exposures. The changes in gene expression, and in pathways regulating host defense, can be used to evaluate how the lung adapts to cigarette smoke exposure. Understanding how the lungs cope with the oxidant burden and the many gaseous and particulate components of cigarette smoke initially and upon repeated exposures is likely to provide information about pathways and processes underlying host defense and the development of chronic lung disease

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