Asthma and chronic obstructive pulmonary disease (COPD) are lung diseases caused by exaggerated lung inflammation in response to exposure to chemical pollutants. These inflammatory responses lead to airway obstruction and ultimately compromised airflow. Both asthma and COPD are highly prevalent diseases that affect women disproportionally. Over 25 million (or 1 in 12 Americans) have asthma, a number that is steadily on the rise, and its morbidity for females has been reported to be at least 62% higher than males. Similarly, COPD is the third leading cause of death worldwide, affecting over 7 billion individuals, and its mortality rate has been steadily rising for the past two decades, especially in women. A definitive link between long term exposure to ambient air pollution and the development of lung disease has been difficult to determine as multiple confounding variables have been observed in longitudinal studies attempting to examine this correlation. However, the direct effect of specific air pollutants on promoting the development of these airway diseases, and the causes of the observed gender disparities in their prevalence have not been elucidated. Environmental factors that have been shown to increase the risk of asthma and COPD include ozone, particulate matter, cigarette smoke, and allergens derived from cockroach, dust mite, mice, and rats. The impact of these factors, and the mechanisms involved in the observed sex disparities for both diseases remain unknown. To this end, our lab has recently challenged male and female C57/BL6 mice with a house dust mite (HDM) solution containing two HDM species, Dermatophagoides pteronyssinus and Dermatophagoides farinae. Our preliminary findings showed alterations in respiratory mechanics and an up-regulation of immune responses that were different between male and female animals following HDM challenge. These models have recapitulated many of the pathologic characteristics observed in human asthma and COPD patients, including airway neutrophilia, airway hyperresponsiveness (AHR), compromised vascular barrier function and lower airway remodeling including emphysema. This indirect examination revealed sex differences in airway inflammation and remodeling. The goal of this proposal is to characterize the degree of inflammation and remodeling in HDM-challenged animals with a more objective and quantitative methodology, using two-photon microscopy techniques. With these, we may acquire a deeper understanding of the cell-specific effects of environmental exposures on male and female mice. We will also extend the characterization of the inflammatory response using flow cytometry in order to identify differences in metabolic state and phenotype of alveolar epithelial cells and macrophages. The knowledge gained can be applied to models of ozone-induced lung inflammation. This information could lead to better diagnostic tests, individualized treatment options, and identification of sex-specific environmental and hormonal triggers that lead to severe lung disease symptoms.
There is a clear involvement of environmental components in the induction and exacerbation of respiratory diseases including chronic obstructive pulmonary distress syndrome (COPD) and asthma. Disparities in sensitivity to these factors between males and females have been identified, but the structural basis of these differences have not been examined by complex imaging techniques. Here, we will use two-photon microscopy to identify changes that could lead to better diagnostic tests and individualized treatment options for patients with inflammatory lung disease, while identifying the environmental and hormonal triggers that lead to severe symptoms.
|Fuentes, Nathalie; Silveyra, Patricia (2018) Endocrine regulation of lung disease and inflammation. Exp Biol Med (Maywood) :1535370218816653|