39 - Using electrophilic fatty acid derivatives to tame host-induced lung injury during influenza infection

Abstract

In the past century, there have been four major Influenza A Virus (IAV) pandemics including the H1N1 strain that killed an estimated 50 million people in 1918. Seasonal strains still claim over 250,000 deaths globally each year and circulating strains in migratory birds and poultry that could potentially mutate and transmit in humans, are known to be highly pathogenic with reported mortality rates of over 50%. In cases of severe infection, an exuberant host-response induces lung injury by generating reactive oxygen and nitrogen species, recruiting immune cells, and damaging the epithelial-endothelial barrier. Vaccines and antiviral treatments do not focus on host-mediated lung injury; therefore, novel therapeutic strategies that target the host to minimize lung damage are required. Electrophilic fatty acid derivatives (EFADs) can dampen inflammation through nuclear factor κB (NF-ĸB) inhibition as well as activate antioxidant responses via nuclear factor erythroid 2-related factor 2 (Nrf2) by alkylating key cysteine residues involved in redox signaling. We hypothesized that EFADs will mitigate IAV-induced lung injury by dampening inflammation (NF-ĸB) and activating antioxidant responses (Nrf2). Our group successfully used nitro-oleic acid (NO2-OA, an EFAD) to mitigate lung injury observed 70% survival of NO2-OA treated mice versus 10% survival in those treated with the vehicle. A significant decrease in both CD4 and CD8 T cell recruitment was observed on day 6 post infection and correlated with maximal plasma levels of NO2-OA. Furthermore, pilot study data showed decreased Nrf2 nuclear translocation during infection and subsequent restoration upon treatment with NO2-OA. Together, these data suggest EFADs can rescue mice infected with a lethal dose of IAV and both NF-ĸB and Nrf2 are possible mechanisms of action since they are implicated in immune cell infiltration through their ability to alter the expression of genes associated with cytokine/chemokine release, reaction oxygen and nitrogen species generation, and antiviral signaling. These studies will shed light on how EFADs can “tame” the host response to dampen the collateral damage associated with severe infection and how both Nrf2 and NF-ĸB are regulated during influenza infection.