Trauma and surgery patients who survive an initial bout of hemorrhagic shock frequently develop complications related to infection. The mortality of sepsis among critically ill traumatized and surgical patients is extremely high, largely because the underlying disease pathogenesis is incompletely understood. In an effort to develop a therapeutic strategy for post-trumatic sepsis, the PI designed and synthesized a tetravalent guanylhydrazone (""""""""TG,"""""""" or """"""""CNI-1493"""""""") inhibitor of macrophage activation. CNI-1493 effectively prevents the synthesis of multiple proinflammatory mediators (e.g. TNF, IL-1 and NO) that are known to contribute to the lethality of sepsis by preventing the phosphorylation of p38 MAP kinase. A protein that mediates the monocyte-suppressing activity of CNI-1493 has been purified and identified as fetuin, a negative acute phase protein that has previously been implicated as a carrier of biologically active factors. Fetuin now appears to occupy a critical role in the normal counter-regulation of monocytes, and CNI-1493 has proved extremely useful as a molecular tool to study the effects of proximal inhibition of macrophage activation in animal models of sepsis and injury. To date however, the effects of CNI-1493 in a clinically relevant animal model of trauma, injury, or hemorrhagic shock are unknown. Trauma and shock are known to induce a state of altered cytokine responsiveness in which the regulation of proinflammatory mediator synthesis is deranged. The objective of the studies outlined in this proposal is to determine whether CNI-1493 inhibits the synthesis of multiple macrophage- derived mediators in the altered cytokine milieu of post-traumatic sepsis. The experiments proposed in the Specific Aims will define the molecular basis for the binding and uptake of CNI-1493 and fetuin in human and murine monocytes, and characterize the effects of CNI-1493 and fetuin in a clinically relevant model of sepsis in animals previously subjected to surgery and hemorrhagic shock. This experimental design is expected to yield important new information concerning the endogenous mechanisms underlying the counter-regulation of proinflammatory cytokine production, and to identify new therapeutic strategies for the treatment of post-traumatic or post-operative sepsis based on deactivating the macrophage.
Showing the most recent 10 out of 46 publications
