Role of Interleukin-18 in Acute Lung Injury

描述（由申请人提供）： 抗细胞因子治疗急慢性炎症性疾病已进入临床 药目前，基于抗细胞因子的治疗的主要靶点是肿瘤坏死 因子（TNF）和白细胞介素-1（IL-1）、多效性、促炎细胞因子。IL-1b的合成 作为需要称为IL-1b转化酶（ICE，半胱天冬酶-1）的蛋白酶的前体， 裂解和分泌活性IL-1b。一种相对较新的细胞因子，IL-18，也使用ICE， 裂解并分泌成活性细胞因子。IL-18是目前的主要目标。 study. ICE的特异性抑制剂减少了IL-2和IL-3的释放，从而降低了IL-2和IL-3的生物活性。 1b和IL-18。成熟的IL-18在结构上与成熟的IL-1b相似。最初报告为共刺激剂 干扰素-g（IFNg）的生产在小鼠内毒素血症，我们的研究表明， IL-18具有与IL-1b相似的广泛生物学效应，例如诱导 其它促炎细胞因子如趋化因子家族和促炎因子的活化可被抑制。 中性粒细胞与内皮粘附分子的上调。很少有人知道的 IL-18在人和小鼠急性肺损伤（ALI）中的产生和生物学特性 急性肺损伤模型。目前的提案侧重于IL-18生产的性质 从中性粒细胞和激活中性粒细胞在ALI的情况下。我们已经分离出 克隆了特异性中和IL-18生物活性的人IL-18结合蛋白， 18（IL-18结合蛋白，IL-18 BP），并且可能呈递天然存在的IL-18抑制剂。我们建议检查人中性粒细胞中IL-18和IL-18 BP的产生。IL-18引发嗜中性粒细胞产生超氧化物的能力将用作IL-18- 1的指标。 介导的中性粒细胞活化和组织损伤。IL-18 BP阻断IL-18受体活化的能力与IL-18受体活化的程度有关。 通过fMLP产生超氧化物将测试内源性嗜中性粒细胞衍生的IL-18对 在功能上影响产生细胞因子的同一细胞。使用过表达IL- 18 BP时，我们将在LPS和烫伤诱导的ALI模型中激发小鼠。中和 IL-18抗体也将用于揭示内源性IL-18在急性肺损伤中的作用， 小鼠外源性IL-18将通过胃肠外以及吸入给予。IL-的测定 IL-18和IL-18 BP水平与ALI患者的疾病严重程度相关， 对LPS刺激的离体反应。在这些研究中，我们建议检查这种细胞因子在急性炎症性肺病中的作用。这些研究将拓宽目前 ALI的治疗干预。

DESCRIPTION (provided by applicant): Anti-cytokine therapy for acute and chronic inflammatory diseases has entered clinical medicine. The main targets for anti-cytokine-based therapies are presently tumor necrosis factor (TNF) and interleukin-1 (IL-1), pleiotropic, proinflammatory cytokines. IL-1b is synthesized as a precursor requiring a protease called IL-1b converting enzyme (ICE, caspase-1) for cleavage and secretion of active IL-1b. A relatively new cytokine, IL-18, also uses ICE for cleavage and secretion to an active cytokine. IL-18 is the primary objective for the present study. Specific inhibitors of ICE reduce the release and hence the biological activity of both IL- 1b and IL-18. Mature IL-18 is structurally similar to mature IL-1b. Initially reported as a costimulant of interferon-g (IFNg) production in mice during endotoxemia, our studies demonstrate that IL-18 has broad biological effects similar to those of IL-1b such as inducing the synthesis of other pro-inflammatory cytokines such as the family of chemokines and activation of neutrophils with upregulation of endothelial adhesion molecules. Little is known about the production and biological properties of IL-18 in acute lung injury (ALI) in humans and in murine models of acute lung injury. The current proposal focuses on the nature of the IL-18 production from neutrophils and activation of neutrophils in the context of ALI. We have isolated and cloned a human IL-18 binding protein which specifically neutralizes the biological activity of IL- 18 (IL-18 binding protein, IL-18BP) and likely presents the naturally occurring inhibitor of IL-18. We propose to examine the production of IL-18 and IL-18BP in human neutrophils. The ability of IL-18 to prime neutrophils for generation of superoxide will be used as an indicator of IL-18- mediated neutrophil activation and tissue damage. The ability of IL-18BP to block activation of superoxide production by fMLP will test the role of endogenous, neutrophil-derived IL-18 to functionally affect the same cell that produces the cytokine. Using mice overexpressing the IL- 18BP, we will challenge mice in model of LPS and hemorrhage-induced ALI. Neutralizing antibodies to IL-18 will also be used to reveal the role of endogenous IL-18 in acute lung injury in mice. Exogenous IL-18 will be given parenterally as well as by inhalation. Determinations of IL- 18 and IL-18BP levels will be correlated with disease severity in patients with ALI and correlated with ex vivo responses to LPS challenge. In these studies, we propose to examine the role of this cytokine in acute inflammatory lung disease. These studies will broaden the present therapeutic intervention in ALI.