The contributions of murine KC and MIP-2 in hemorrhage induced neutrophil priming for acute lung injury following subsequent septic challenge
Trauma patients represent a significant risk for the development of ALI following exposure to a secondary infectious challenge. This risk is suggested to be associated with an event that "primes" certain members of the immune cell population such that a subsequent/secondary challenge elicits a dys-functional response. Characteristics of ALI are neutrophil sequestration in the lung, delayed neutrophil apoptosis and increased pro-inflammatory cytokines. Chemokines are proteins produced by immune and resident tissue cells in response to inflammation and function as regulators of neutrophil trafficking and cytolytic activity. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are mouse homologues of human neutrophil chemokine, interleukin-8. We hypothesize that KC and MIP-2 produced in response to an initial "priming" event (hemorrhage), serve to alter normal neutrophil function in response to a secondary challenge (sepsis), thereby contributing to the pathogenesis of ALI. To test this hypothesis, a mouse model of hemorrhage-induced "priming" for the development of ALI subsequent to septic challenge was used. In vivo experiments examined the effects of specific chemokine or chemokine receptor antagonism (using neutralizing antibody, gene specific siRNA knock-down and CXCR2 receptor antagonism), immediately following hemorrhage priming. Neutralization and local pulmonary silencing of MIP-2, but not KC, produced significant decreases in pro-inflammatory cytokine levels, neutrophil influx and lung tissue injury. To further investigate the cellular source of these chemokines, neutrophil depleted and macrophage deficient mice were used in our mouse model for ALI. The results from this experiment suggest that both neutrophils and macrophage are necessary for the pathogenesis of ALI in this model. In a separate experiment, neutrophils from hemorrhaged mice, when adoptively transferred to neutrophil depleted mice, were capable of contributing to the development of ALI. Post hemorrhage treatment of donor mice with anti-MIP-2, but not anti-KC significantly reduced ALI and pro-inflammatory cytokine changes in the septically challenged recipient mice. These data support our hypothesis that KC and MIP-2 serve non-redundant regulatory roles in the altering neutrophil function observed in mice following hemorrhage "priming" for ALI subsequent to septic challenge and thus their homologue in humans and its receptor, may represent novel therapeutic targets going forward. ^
Health Sciences, Immunology
"The contributions of murine KC and MIP-2 in hemorrhage induced neutrophil priming for acute lung injury following subsequent septic challenge"
Dissertations and Master's Theses (Campus Access).