Prevention of Trauma/Hemorrhagic Shock-Induced Mortality, Apoptosis, Inflammation and Mitochondrial Dysfunction

We proposed determining if IL-6 merits consideration as a resuscitation adjuvant with Hextend for soldiers suffering from severe battlefield injuries. Our results in rat models demonstrated that IL-6 alone was not sufficient when Hextend is substituted for shed blood as the major resuscitation fluid; rather, soluble IL-6R-alpha must be given with IL-6. Alternatively, hyper-IL-6, a chimeric protein consisting of IL-6 linked to the soluble IL-6R-alpha can substitute for IL-6. Other major findings of our studies were: 1) Leukocyte apoptosis is not sufficiently sensitive to use as a biomarker to guide patient selection for hyper-IL-6, but kidney injury biomarkers may be useful for this purpose; 2) Two proteostasis modulators, Hsp70 and Hsp40, were identified by transcriptome analysis that may mediate the beneficial effects of IL-6 signaling in the liver and lung; 3) In T/HS patients, increased peripheral blood PMN apoptosis is associated with reduced risk of developing infection; 5) IL-6 signaling initiated immediately upon resuscitation in our standard T/HS rat model reduces mortality from Psuedomonas aeruginosa pneumonia through maintenance of Surfactant Protein D levels within the lung, which lends further support to the hypothesis that the beneficial effects of IL-6 signaling extends to protection from infection; 6) Mitochondrial function is improved through IL-6 signaling suggesting another mechanism for the apoptosis-reduction benefit of IL-6 signaling, and 7) Stat3--alpha can substitute for Stat3--alpha to restore mitochondrial function in Stat3-deficient cells indicating, for the first time, that both Stat3 isoforms support mitochondrial function. The original document contains color images.