MYOCARDIAL RESPONSE TO INJURY

三年前，一项白细胞介素-1受体拮抗剂III期临床试验在中期分析确定主要疗效终点无法达到后终止。TNF受体融合蛋白（TNF-R-Fc）在复合TNF方面比单独的单体结合蛋白更有效。直觉上，将TNF-R-Fc输注到脓毒症患者中应使TNF结合到宿主的治疗优势。到目前为止，临床抗细胞因子试验已经证明在机制上是有价值的，但在治疗上是令人失望的，而且很难实现。我们注意到，在临床缺血/再灌注损伤后，人心肌（心房组织）组织TNF增加300%。我们还报道了TNF以剂量依赖性方式抑制心脏收缩功能。白细胞介素（IL-1、IL-6、IL-8、IL-12、IL- 18）和TNF（具有项目IA）的应激诱导令人信服地加重损伤后/全身性炎症。目前的申请是作为我们1998年赠款的拟议目标的延伸而建立的。我们提出IL-18作为一种更接近的心脏抑制细胞因子（项目II，III，IV，V，VIII和IX）。我们假设：损伤后促炎性和抗炎性TNF和IL-18表达之间的动态平衡（正反馈）提供了允许减轻创伤后心肌功能障碍的治疗机会。虽然IL-18目前被认为是一种有效的免疫调节细胞因子，但我们推测：a）IL-18是在应激/损伤/损伤后产生的; c）内源性心肌TNF激活CASPACE-1依赖性和非依赖性机制，将IL-189原切割为IL-18; B）IL-18原组成性存在于心脏组织和外周血单核细胞中; d）IL-18是有效的负性肌力细胞因子，和e）抑制IL-18产生或拮抗IL-18的策略将减轻创伤后心脏功能障碍。

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.