Author ORCID Identifier

0000-0002-7749-9781

Date of Graduation

5-2017

Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michael Blackburn, PhD

Committee Member

Russell Broaddus, MD PhD

Committee Member

Shane Cunha, PhD

Committee Member

Amber Luong, MD PhD

Committee Member

Yang Xia, MD PhD

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects 5 - 8 million individuals worldwide and 200,000 individuals in the United States alone. Although prevalent, we do not know what causes IPF and no effective curative treatment exists for this disease. Our laboratory has shown that extracellular accumulation of adenosine and subsequent activation of the adenosine 2B (ADORA2B) receptor promotes immune cell invasion, airspace destruction, and fibrosis in chronic lung disease. Additionally, alternatively activated alveolar macrophages (AAMs) expressing ADORA2B, have been implicated in mediating adenosine’s pro-fibrotic effects in IPF. However, the exact role of AAMs in the hypoxic lungs of IPF patients is not known. Our results reveal myeloid-specific ADORA2B deletion, antagonism of ADORA2B on AAMs, and inhibition or genetic silencing of hypoxia inducible factor 1a (HIF1A) as a means to attenuate pro-fibrotic mediator production and pulmonary fibrosis in bone marrow derived macrophages (BMDMs) and in vivo models of bleomycin-induced pulmonary fibrosis. These players will be valuable as potential clinical targets to halt differentiation of macrophages into the reparative AAM subtype and attenuate their subsequent pro-fibrotic role. Ultimately, these investigations will lead to a better understanding of adenosine’s role in IPF and lead to identification of targets for novel therapeutics that can prevent disease progression and possibly reverse lung fibrosis.

Keywords

idiopathic pulmonary fibrosis, adenosine, alternatively-activated macrophages, hypoxia-inducible factor 1-alpha, acute lung injury

Available for download on Friday, April 13, 2018

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