Is Upregulated by Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models
Matrix metalloproteinase-12 () is upregulated by cigarette smoke (CS) and plays a critical role in extracellular matrix remodeling, a key mechanism involved in physiological repair processes, and in the pathogenesis of emphysema, asthma, and lung cancer. While cigarette smoking is associated with the development of chronic obstructive pulmonary diseases (COPD) and lung cancer, exposures to CS and second-hand smoke (SHS) are associated with asthma development in the offspring. SHS is an indoor air pollutant that causes known adverse health effects; however, the mechanisms by which SHS exposures predispose to adult lung diseases, including COPD, asthma, and lung cancer, are poorly understood. In this study, we tested the hypothesis that SHS exposure aggravates adult-induced emphysema, asthma, and lung cancer. Pregnant BALB/c mice were exposed from gestational days 6-19 to either 3 or 10mg/m of SHS or filtered air. At 10, 11, 16, or 17weeks of age, female offspring were treated with either saline for controls, elastase to induce emphysema, house-dust mite (HDM) to initiate asthma, or urethane to promote lung cancer. At sacrifice, specific disease-related lung responses including lung function, inflammation, gene, and protein expression were assessed. In the elastase-induced emphysema model, SHS-exposed mice had significantly enlarged airspaces and up-regulated expression of (10.3-fold compared to air-elastase controls). In the HDM-induced asthma model, exposures to SHS produced eosinophilic lung inflammation and potentiated gene expression (5.7-fold compared to air-HDM controls). In the lung cancer model, exposures to SHS significantly increased the number of intrapulmonary metastases at 58weeks of age and up-regulated (9.3-fold compared to air-urethane controls). In all lung disease models, upregulation was supported at the protein level. Our findings revealed that SHS exposures exacerbate lung responses to adult-induced emphysema, asthma, and lung cancer. Our data show that MMP12 is up-regulated at the gene and protein levels in three distinct adult lung disease models following SHS exposures, suggesting that MMP12 is central to SHS-aggravated lung responses.
Publication Source (Journal or Book title)
Frontiers in physiology
Noël, A., Perveen, Z., Xiao, R., Hammond, H., Le Donne, V., Legendre, K., Gartia, M. R., Sahu, S., Paulsen, D. B., & Penn, A. L. (2021). Is Upregulated by Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models. Frontiers in physiology, 12, 704401. https://doi.org/10.3389/fphys.2021.704401