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Formation and signaling of electrophilic lipids in immunity

Buchan, Gregory (2019) Formation and signaling of electrophilic lipids in immunity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Many diseases are caused by aberrant inflammation. Novel drug strategies are transitioning from global suppression and single-target inhibition to fine tuning the immune response by modifying several key pathways in order to minimize tissue injury. Recently, classes of pleiotropic, electrophilic lipids (mainly nitroalkenes and α, β-unsaturated ketones), are emerging as prominent immunomodulators that both dampen inflammation and initiate cytoprotective responses. Electrophilic lipids alkylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) causing a decrease in inflammation. Furthermore, kelch-like ECH-associated protein 1 (Keap1) is also alkylated by electrophilic lipids, causing the release of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the activation of hundreds of genes involved in repairing and preventing cellular injury.
Moreover, endogenous lipid mediators such as Lipoxin A4 (LXA4) have successfully limited tissue injury in animal models of sepsis, acute lung injury, and asthma. The primary metabolite of LXA4, 15-oxo-LXA4, is electrophilic and its role in immune responses is understudied. Herein, I demonstrate that 15-oxo-LXA4 acts in a similar manner to other electrophilic lipids and limits LPS-induced inflammatory responses in murine macrophages. These data suggest electrophilic metabolites of endogenous lipid mediators such as LXA4 may be partially responsible for their anti-inflammatory and cytoprotective actions.
Nitroalkenes alkylate NF-ĸB and Keap1, resulting in dampened inflammatory responses and active tissue repair. In fact, Nitro-Oleic Acid (NO2-OA) is currently in clinical trials for focal
v
segmental glomerulosclerosis, asthma and pulmonary hypertension. Much of the preclinical research for nitroalkenes has been carried out in epithelial, endothelial, or macrophages so their effect on dendritic cell function is largely unknown. The data provided within suggest that NO2-OA limits DC activation. These changes are consistent with other electrophilic lipids and suggest a common role in modifying immune responses.
Lastly, I tested the efficacy of NO2-OA in treating influenza-induced lung injury in mice. Survival increased compared to vehicle controls and pro-inflammatory cytokine production was decreased. These results demonstrate the potential of NO2-OA to improve outcomes of severe viral infection, characterized by aberrant inflammation. Further research on NO2-OA, 15-oxo-LXA4 and other electrophiles will enhance the knowledge of these agents and inform future clinical trials and drug discovery efforts.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Buchan, Gregorygrb44@pitt.edugrb44
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKensler, Thomastkensler@pitt.edu
Thesis AdvisorFreeman, Brucefreerad@pitt.edu
Thesis AdvisorWendell, Stacygstacy@pitt.edu
Committee MemberBinder, Robertrjb42@pitt.edu
Committee MemberKinchington, Paulkinchingtonp@upmc.edu
Committee MemberLakdawala, Seemaseemal@pitt.edu
Date: 30 December 2019
Date Type: Publication
Defense Date: 8 November 2019
Approval Date: 30 December 2019
Submission Date: 17 December 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 164
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: electrophilic lipid, inflammation, dendritic cell, resolution
Date Deposited: 30 Dec 2019 14:31
Last Modified: 30 Dec 2019 14:31
URI: http://d-scholarship.pitt.edu/id/eprint/38065

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