The Hypoxic Adenosine Response Modulates Macrophage Differentiation and Contributes to Lung Disease

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Philip, Kemly Mary
• <p><a href="http://orcid.org/0000-0002-7749-9781" target="_blank">0000-0002-7749-9781</a></p>

Contributors dc:contributor

• Michael Blackburn, PhD
• Russell Broaddus, MD PhD
• Shane Cunha, PhD

• idiopathic pulmonary fibrosis
• adenosine
• alternatively-activated macrophages
• hypoxia-inducible factor 1-alpha
• acute lung injury
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/734

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1782