B30-02 Evaluation of TREM-1 Therapy as a Medical Countermeasure for Inhalation Sulfur Mustard in Male Sprague Dawley Rats

Rationale Inhaled sulfur mustard (SM) causes severe toxicity, with respiratory complications considered the primary determinant of mortality and morbidity. There is currently no FDA-approved SM therapeutic available. We hypothesized that blockade of TREM-1, an inflammation amplifier, would ameliorate SM toxicity. In this study, two TREM-1 inhibitory peptides, GF9 and GA31 formulated in macrophage-targeted lipopeptide complexes (LPC), currently in development to treat cancer, sepsis, retinopathy, pertussis, acute respiratory distress syndrome, rheumatoid arthritis and other inflammation-associated diseases and conditions, were evaluated for attenuation of mortality and lung inflammation following an inhaled SM 28-day LD50 (0.8 mg/kg) exposure in intubated male Sprague Dawley rats. GF9 targets TREM-1 on all myeloid cells, while GA31-LPC - predominantly targets TREM-1 on macrophages. Methods Vehicle, 25 mg/kg GF9, or 13 mg/kg GA31-LPC were intraperitoneally administered at 0.5 and 4 hours post-challenge, then daily for 7 days. Efficacy was evaluated through 28 days post-challenge. Results At 7 days post-challenge, 31%, 54% and 77% survival were observed in vehicle, GF9, and GA31-LPC groups, respectively. Survival at 28 days continued to be highest in GA31-LPC group (54%) compared to vehicle (31%) and GF9 (38%) groups. Additionally, peripheral oxygen saturation was significantly increased in GA31-LPC animals at 1 and 7 days post-challenge. In evaluating attenuation of lung inflammation and injury, efficacy was not observed with GF9 or GA31-LPC for cytokine levels in bronchoalveolar lavage fluid (BALF) at 3- or 28-days. However, total cell counts in BALF were decreased at 3 days in GA31-LPC animals compared to vehicle controls. Anatomic pathology revealed dark red and/or mottled discoloration in the lungs of SM exposed animals with attenuation of gross lung injury in GF9 animals 28 days post-challenge (discoloration observed in 20% of GF9 animals compared to 25% and 71% in vehicle and GA31-LPC groups, respectively). Conclusions Overall, decreased mortality was found in GA31-LPC treated animals while decreased lung injury by anatomic pathology was revealed in GF9 treated animals. Combination and longer treatment regimens may be needed for more complete protection from inhalation SM injury.