Author ORCID Identifier

0000-0002-2568-2867

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Holger Eltzschig, M.D., Ph.D.

Committee Member

Farrah Kheradmand, M.D.

Committee Member

Cynthia Ju, Ph.D.

Committee Member

Harry Karmouty-Quintana, Ph.D.

Committee Member

Edgar T. Walters, Ph.D.

Abstract

Acute lung injuries (ALI) can result from both direct insults (e.g. pneumonia or inhalation injury), or systemic conditions such as sepsis or trauma. Current treatment options for patients are limited to supportive care and novel approaches are urgently needed. Appreciating the role of excessive inflammation that underlies the pathophysiology of ALI, we sought to identify endogenous mechanisms that dampen inflammation. Here we investigated two pathways that worked to limit excessive pulmonary inflammation in myeloid cells using a mouse model of sepsis-associated ALI. In the first approach we screened for microRNAs during the recovery phase of ALI that could potentially regulate inflammation. We found that miR-147 is highly expressed during the recovery phase of ALI and worked to dampen inflammation by targeting the mitochondrial subunit, NDUFA4, which resulted in an accumulation of succinate in macrophages. Succinate in turn inhibited the demethylation of Histone H3 to silence the expression of inflammatory cytokines. In the second approach, we demonstrate that the neuronal guidance protein, Netrin-1, is highly expressed in infiltrating alveolar macrophages after the onset of ALI. Netrin-1 deletion in the myeloid compartment resulted in exacerbated ALI and increased NK cell recruitment, which was dependent on the upregulation of the chemokine, CCL2, in the alveolar space. Together, the studies described in this dissertation point to two previously unappreciated mechanisms that serve to limit the pro-inflammatory processes of macrophages and limit tissue damage during ALI. Future work focused on leveraging these processes have great potential to guide the development of novel treatments for ALI.

Keywords

acute lung injury, microRNA, inflammation, macrophages, Netrin-1

Available for download on Wednesday, April 27, 2022

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