Damp-Mediated Innate Immune Failure and Pneumonia After Trauma

Injury resulting from combat trauma dramatically impacts the host immune response. Combat wounds release Damage Associated Molecular Patterns (DAMPs) and importantly infection of the host is more common after injury. This program studies how DAMPs alter the immune response to trauma through the study of specific patient populations, highly correlative animal models, computational modeling and statistics and molecular mechanisms of action, all focused toward identifying therapeutic targets. We have assembled a group of laboratories that have each previously studied individual DAMPs and their impact on innate immunity. Project 1 studies mitochondrial formyl peptides and DNA. Project 2 studies heme and its gasotransmitter product, carbon monoxide. Project 3 studies extracellular purinergic signaling. Project 4 studies the alveolar physicochemical environment. Project 5 studies oligonucleotides and global immune phenotypic alterations by injury. Project 6 studies the roles of complement and reactive oxygen species and computational modeling. Each laboratory has made tremendous progress in their own project, which has been amplified through integrated collaborative efforts. Year one allowed us: 1. to establish a biorepository that collected nearly 100 clinical specimens, 2. characterize the animal model of trauma+infection, 3. assess human and murine neutrophil functional assays and correlate with in depth phenotyping through CyTOF, 4. assess purinergic changes in patient cells and serum and 5. present and publish our findings at numerous scientific meetings and peer reviewed reports as well as applications for further funding. Uniquely, all studies evaluate immunity both in the circulation and the alveolus that allows us to study the impact of trauma on acute lung injury and bacterial pneumonia. Because of the enormous scope of the interactive data sets created, results are evaluated using our unified computational modeling core.