Three years ago, a phase III interleukin-1 receptor antagonist trial was terminated after interim analysis determined that the primary efficacy end points would not be met. The TNF receptor fusion protein (TNF-R-Fc) is more effective at complexing TNF than either of the monomeric binding proteins alone. Intuitively, infusion of TNF-R-Fc into a septic patient should bind TNF to the therapeutic advantage of the host. Clinical anti- cytokine trials have, to date, proven mechanistically valuable, but therapeutically-disappointing-and very hard to accomplish. We note tissue TNF increases by 300% in human myocardium (atrial tissue) following a clinical ischemia/reperfusion insult. We have also reported that TNF depresses cardiac contractile function in a dose dependent fashion. The stress induction of interleukins (IL-1, IL-6, IL-8, IL-12, IL- 18) and TNF (with Project IA) persuasively exacerbate the post- injury/systemic inflammation. This current application is founded as an extension of the proposed goals of our 1998 grant. We propose IL-18 as an even more proximal cardiodepressive cytokine (with Projects II, III, IV, V, VIII and IX). We postulate that: The dynamic balance (positive feedback) between post- injury pro- and anti-inflammatory TNF and Il-18 expression provides therapeutic opportunities permitting attenuation of post-traumatic myocardial dysfunction. Although IL-18 is currently accepted as a potent immunomodulatory cytokine, we postulate that: a) IL-18 is proposed following stress/injury/insult; c) endogenous myocardial TNF activates both CASPACE-1 dependent and independent mechanisms of cleaving pro-IL-189 to IL-18; b) pro-interleukin-18 is present constitutively in cardiac tissue and peripheral blood monocytes; d) IL-18 is a potent negatively inotropic cytokine and e) strategies to inhibit IL-18 production or antagonize IL-18 will attenuate post-traumatic cardiac dysfunction.
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