Nosocomial pneumonia is the major cause of death at the hospitals among seriously injured trauma patients, though the link between injury and development of nosocomial pneumonia is still not well recognized. Our preliminary results strongly suggest that mitochondrial damage-associated molecular patterns (mtDAMPs) released after tissue injury play a major role in the onset of nosocomial pneumonia by attracting polymorphonuclear neutrophils (PMN) to the injury site and thus decreasing the pool of PMN available for killing bacteria in lungs, hence leading to development of pneumonia. Indeed, our data demonstrate that bacteria are cleared from the lungs of healthy animals but not injured animals. In addition, exposure of PMN to mtDAMPs results in desensitization of N-formylated-peptide receptor 1 (FPR-1) as well as other chemokine receptors (via homo- and heterologous desensitization) leading to limiting recruitment of PMN to the lungs after bacterial infection. Thus inhibition of FPR-1 function soon after injury could prevent PMN chemotaxis to the site of injury and desensitization of chemokine receptors, and thus could be a good therapeutic strategy allowing PMN to respond to the chemokines released from the cells in the lungs during bacterial infection. Our preliminary data also indicate that simultaneous application of bacteria and syngeneic PMN after injury improves bacterial clearance in mouse lungs. Therefore, we propose an innovative and simple treatment of direct delivery of PMN to the lungs. Our ultimate goal is to establish the methods for prevention and/or treatment for nosocomial pneumonia in seriously injured people. We hypothesize that inhibition of PMN chemotaxis toward mtDAMPs released at the site of injury and/or direct administration of PMN to the lungs will prevent development of nosocomial pneumonia in trauma patients. Thus we list two specific aims as shown below.
Specific Aim 1. Investigate whether blocking of FPR-1 increases PMN migration to the infected lungs and enhances bacterial clearance Hypothesis: Blocking of PMN migration to the site of injury increases a pool of PMN migrating to infected lungs.
Specific Aim 2. Establish whether intratracheal PMN infusion clears lung bacteria in mice after injury Hypothesis: Delivery of active PMN to infected lungs will prevent pneumonia. !
Many seriously injured trauma patients develop nosocomial pneumonia at intensive care unit and no real mechanistic cause is understood. We plan to establish unique and innovative methods to prevent/treat nosocomial pneumonia after injury without antibiotics based on our understanding of neutrophil signaling pathways after injury.
