Prevention of Trauma/Hemorrhagic Shock-Induced Mortality,Apoptosis, Inflammation and Mitochondrial Dysfunction
Annual rept. 5 Nov 2012-4 Nov 2013
BAYLOR COLL OF MEDICINE HOUSTON TX
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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. must be given with IL-6. Alternatively, hyper-IL-6, a chimeric protein consisting of IL-6 linked to the soluble IL-6R., 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 THS 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 THS 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. can substitute for Stat3. to restore mitochondrial function in Stat3-deficient cells indicating, for the first time, that both Stat3 isoforms support mitochondrial function.
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