- Restrictions on Access:
- Restricted (Penn State Only).
- Studies on air pollution exposure have reported more negative lung health outcomes for women than men and have identified both hormonal and environmental factors as potential drivers of these sex and gender differences. However, sex-dependent immune gene expression patterns, regulatory networks, and mechanisms underlying lung inflammation and mechanics have not been well studied. The overall hypothesis of my thesis work is that female sex hormones, specifically gonadal hormones, control mechanisms of ozone-induced lung inflammation and airway hyperresponsiveness (AHR). To test this hypothesis, we first characterized lung gene and miRNA expression networks associated with previously observed sex differences in ozone-induced lung inflammation. We exposed adult C57BL/6J male and female mice (including females at different stages of the estrous cycle) to ozone or filtered air (FA; control). We performed miRNA transcriptome analyses in lung tissue by PCR arrays. We identified differences in biological networks in male and female mice, and across the estrous cycle. These were affected by ozone exposure, indicating that both sex and hormonal status influence posttranscriptional regulation of gene expression in response to ozone. We then investigated whether fluctuations in circulating hormone levels occurring in the estrous cycle affect the inflammatory response to ozone exposure. We found a differential inflammatory response to ozone in females exposed in the luteal phase (low estrogen levels) vs. the follicular phase (high estrogen levels). Females exposed to ozone in the follicular phase had significantly higher expression of inflammatory genes, lung injury and AHR, and displayed differential activation of regulatory pathways than females exposed in the luteal phase. This led us to hypothesize whether 17-estradiol regulates ozone-induced AHR and inflammation. To test this, we performed gonadectomy and 17-estradiol replacement in male and female mice followed by ozone exposure. We compared lung function parameters, lung injury and inflammation markers. The results revealed significantly higher AHR and inflammation in female mice after ozone exposure. Ovariectomy reduced ozone-induced AHR and inflammation, which was restored by 17-estradiol treatment, indicating that 17-estradiol contributes to inflammatory responses and AHR triggered by ozone. Finally, we evaluated sex differences in a mouse model of asthmatic inflammation. We challenged both male and female mice with house dust mite (HDM), a common allergen for 5 weeks to trigger an allergic asthma phenotype. Our findings showed an increase in airway resistance and activation of the immune response following HDM challenge in both males and females. Interestingly, the differences observed in immune cells and gene expression patterns triggered by HDM treatment suggest that the response in males is predominantly eosinophilic, while the response in females is mostly neutrophilic. We conclude that gonadal hormones (e.g. 17-estradiol) play sex-specific roles in the control of mechanisms of lung inflammation and AHR activated by environmental challenges.
- Dissertation Note:
- Ph.D. Pennsylvania State University 2019.
- Technical Details:
- The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
View MARC record | catkey: 27087997