LAUSR

INTRODUCTION Burn injury induces multiple signaling pathways leading to a significant inflammatory storm that adversely affects multiple organs, including the heart. PARP1 inhibition, with specific agents such as PJ34, is effective in reducing oxidative stress and cytokine expression in the heart. We hypothesized that PARP1 inhibition would reduce inflammatory signaling and protect against burn injury induced cardiac dysfunction. METHODS Male Sprague-Dawley rats (8-week-old, 300-350 gms) were randomized to Sham injury (Sham), 60% TBSA burn (24hpb), or 60% TBSA burn with IP administration of PJ34 (20mg/kg, 24hpb + PJ34) and sacrificed 24 hours post injury. Cardiac function was determined using Vevo 2100 echocardiography (ECHO). Genetic expression of 84 specific TLR-mediated signal transduction and innate immunity genes were examined using microarray to evaluate cardiac tissue. Qiagen GeneGlobe Data Analysis Center was used to analyze expression and genetic clustering was performed using TreeView V2.0.8 software. Real-time qPCR was utilized to validate identified differentially expressed genes. RESULTS Burn injury significantly altered multiple genes in the TLR signaling, IL-17 signaling, TNF signaling, and NF-κB signaling pathways and led to significant cardiac dysfunction. PARP1 inhibition with PJ34 normalized these signaling pathways to sham levels as well as improved cardiac function to sham levels. CONCLUSIONS PARP1 inhibition normalizes multiple inflammatory pathways that are altered after burn injury and improves cardiac dysfunction. PARP1 pathway inhibition may provide a novel methodology to normalize multiple burn injury induced inflammatory pathways in the heart.