Research Article: Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice

Date Published: February 28, 2019

Publisher: Public Library of Science

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


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.

Partial Text

Cigarette smoke is a leading health hazard and causes an enormous impact on lung health. Cigarette smoking has long been known to have a significant impact on respiratory health and diseases [1, 2]. Smoking is the number one cause of lung cancer and chronic obstructive pulmonary disease (COPD), and it increases the odds of developing either chronic bronchitis or emphysema [2, 3]. More than 16 million Americans are currently living with a tobacco smoke-related disease, resulting in nearly $170 billion in direct healthcare costs annually [2, 4].

Understanding how the lungs cope with cigarette smoke following a single exposure and upon repeated exposures provides information about pathways and processes underlying host defense that is likely to be useful in understanding the development of chronic lung disease. Cigarette smoke is thought to act initially through the generation of lung cell damage due to oxidants present in the gaseous and particulate phases that initiate host defense. 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.




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