Browsing School, Graduate by Subject "p5779"
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Immunologic and pathogenic interactions between burned mice and Pseudomonas aeruginosaFire is a pinnacle staple of human life. Consequently, burn injuries are inevitable. People that survive the initial burn trauma are at higher risk of severe complications due to secondary bacterial infections from either environmental exposure or hospital-acquired infections. The most common Gram negative bacterium found in burn wounds worldwide is Pseudomonas aeruginosa (PA). Here we employ a non-lethal 10% total body surface area flame-burn. A superimposed infection with PA strain M2 resulted in 100% mortality post-burn with a reduction in the lethal dose from >106 to <102 CFU when administered in the burn site immediately after the burn. This reduction in LD50 only lasts for 72 hours post-burn, suggesting the burn caused a transient reduction in host defenses that reduced the ability to fight infection. This model allowed for the discrimination between immunological events caused by the burn itself and subsequent bacterial infection. We determined that a high concentration of High Mobility Group Box 1 (HMGB1), a danger-associated molecular pattern, was released into the circulation directly after the burn. This release of HMGB1 into the circulation was independent of infection and preceded detectable cytokine responses. With infection, there was a 10-fold increase in circulating HMGB1 that continued until death. The inhibition of circulating HMGB1’s ability to cause inflammatory signaling through the TLR4-signaling pathway with a small molecule inhibitor, P5779, almost doubled the mean time to death and even resulted in a group of survivors. During routine necropsy post-burn, we identified a previously undescribed seroma. The seroma fluid supported the robust growth of PA and recruited neutrophils from the circulation, possibly sequestering them from vital organs at a critical time, thus facilitating burn wound sepsis. This sublethal mouse burn model enabled the study of effects from the burn injury on both the innate response to the burn and the pathogen.