James P. O’Brien
Nitro-Oleic Acid, an Electrophilic Fatty Acid Nitroalkene Derivative, Regulates Innate Immune Cell Metabolism and Attenuates Effector Function in a Murine Model of LPS-Induced Acute Lung Injury
Acute lung injury (ALI) is characterized by a rapid inflammatory response that results in respiratory failure. Multiple conditions, including pneumonia, sepsis, and shock, can cause ALI, ultimately leading to death in 30-50% of cases. Despite pharmacological advances in targeting the immune system, there is still no effective treatment for ALI. Herein, a novel approach to treat ALI is proposed that leverages the pleiotropic anti-inflammatory properties of a bioactive fatty acid, nitro-oleic acid (NO2- OA). NO2-OA attenuates inflammatory responses by targeting two molecules within the cell, nuclear factor (NF)- kB and nuclear factor (erythroid-derived 2)-like 2 (NRF2)-regulated gene. Furthermore, activation of the immune system is accompanied by changes in the metabolism of immune cells. Critical for this metabolic change are two proteins—inducible nitric oxide synthase (iNOS) and NRF2, known targets of NO2-OA. Initial work in this research project demonstrates that NO2-OA suppresses immune cell activation and alters the metabolism of these cells. This research is designed to define the mechanisms accounting for NO2-OA regulation of immune cell metabolism in a manner that limits inflammation in ALI. It is hypothesized that NO2-OA alters metabolism in active immune cells and thereby reduces inflammation.
I’m deeply grateful for this opportunity to grow as a physician-scientist. My time as a Paul Calabresi Medical Student Fellow has allowed me to combine my scientific interests and work at the nexus of immunology, pharmacology, and metabolism. The PhRMA Foundation provided me with the ideal training opportunity for developing a career as a physician-scientist.