Semester

Fall

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Salik Hussain

Committee Member

Paul Lockman

Committee Member

Lori Hazlehurst

Committee Member

John M. Hollander

Committee Member

Ahmad Hanif

Abstract

Air pollution poses a significant threat to public health. It is a mixture of particulate matter, gaseous substances, and other secondary substances. Despite epidemiological research indicating the interactive effects of various components of air pollution, existing studies and regulatory limits often focus on single-exposure scenarios. The emerging understanding of the microbiome’s role in regulating immune response, metabolism, and pathophysiology of various diseases points towards interactions between environmental exposures and microbial dysbiosis. In this dissertation, mice were exposed to relevant deposited doses of carbon black (CB) and ozone (O3), and lung inflammation as well as the lung-gut axis of the microbiome alterations were studied. We also studied the role of nucleotide-biding oligomerization domainlike receptor X1 (NLRX1) in mechanistically modulating immune response and microbial balance. Our project involved inhalation exposures, a unique mouse model (NLRX1 knock out), flow cytometric analysis of immune cells, 16s rRNA sequencing, and absolute bacterial load analysis using QIAcuity digital PCR. We demonstrated significant induction of pulmonary inflammatory response after acute CB+O3 co-exposure coupled with reduced diversity indices and a pathogenic bacterial enrichment in the lung microbiome. In contrast, a significant increase in gut bacterial load, abundance of beneficial bacteria, and induction of microbiome-derived secondary metabolites in the systemic circulation indicated a homeostatic shift. Sub-chronic exposure to CB+O3 did not show significant alterations in the inflammatory response and microbiome balance. However, aggravated inflammatory response and microbiome alterations were observed when lungs were challenged with bleomycin post-exposure. A significant role of genetics, exposure, and sex was observed that changed dynamically at different post-exposure time points. In summary, these studies improved the current understanding of particle and gas mixed exposures in terms of their impacts on immune cell profiling, oxidative stress, and microbiome regulation. Furthermore, our project highlighted the role of microbiome alterations in the air pollution-induced exacerbation of lung inflammation and injury identifying a potential role of the lung-gut axis.

Embargo Reason

Publication Pending

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Available for download on Friday, December 06, 2024

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