Mechanism of delayed phase of increased vascular permeabitity in acute inflammation

为了探讨急性炎症时血管通透性增高的机制，我们建立了重组细胞因子，包括白介素1β、肿瘤坏死因子α、白介素1受体拮抗剂、白介素8、生长刺激癌基因、单核细胞趋化蛋白1及其抗体，并建立了免疫分析系统。本研究以兔内毒素胸膜炎模型为模型，以上述材料和方法为基础，根据以下一系列证据，确定了白细胞介素8作为急性炎症IVP延迟时相的直接介导物：(1)我们再次证实，与其他类型的急性炎症一样，IVP在内毒素诱导的胸膜炎中呈现出类似于其他类型急性炎症的双时相模式，且即刻时相是由组胺介导的。(2)用相应的抗体阻断肿瘤坏死因子α或IL-8均可使延迟性通透性消失，但不影响即刻通透性的持续时间和强度。IL-1ra不能抑制延迟性IVP。(3)中性粒细胞耗竭兔未观察到延迟性通透性，但维持了肿瘤坏死因子α的产生。(4)胸膜腔内注射重组肿瘤坏死因子α或IL-8均可引起延迟型IVP，而抗组胺药对其无抑制作用。(5)注射肿瘤坏死因子α可诱导IL-8的产生。(6)IL-8可诱导去中性粒细胞兔迟发性IVP，而肿瘤坏死因子α无此作用。(7)GRO通过诱导肿瘤坏死因子α的产生而诱导迟发性IVP。因此，肿瘤坏死因子α诱导的IL-8参与了脂多糖诱导的兔迟发性胸膜炎的发病机制。这一机制可能普遍适用于多种类型的急性炎症，因为在体内不同部位的炎症中也观察到了相似的IVP，即关节腔和玻璃体间隙，以及不同刺激条件下的炎症，即兔的尿素晶体。

To investigate the mechanism of increased vascular permeability (IVP) in acute inflammation, we developed the recombinant cytokines, including interleukin (IL)-1β, tumor necerosis factor-α (TNFα), IL-1receptor antagonist (IL-1a), IL-8, growth stimulating oncogene (GRO), monocyte chemoattractant protein-1 (MCP-1) and their antibodies, together with immunoassay systems. Using rabbits with LPS-induced pleurisy as well as the above mentioned materials and methods, we determined interleukin (IL)-8 as a direct mediator for delayed phase of IVP in acute inflammation on the basis of the following series of evidence ; (1) We reconfirmed that the IVP showed biphasic pattern in the LPS-induced pleurisy similarly to the other types of acute inflammation, and the immediate phase is mediated by histamine. (2) Either blocking of TNFα or IL-8 with corresponding antibodies, resulted in disappearance of the delayed permeability, while the duration and the degree of intensity of immediate permeability was not affected. IL-1ra did not suppress the delayed IVP.(3) The delayed permeability was not observed in neutro-phil-depleted rabbits, but the production of TNFα was maintained. (4) Intrapleural injections of either rabbit recombinant TNFα or IL-8 induced a delayed type of IVP that was not inhibited with antihistamine. (5) Injection of TNFα induced the production of IL-8. (6) IL-8 but not TNFα induced the delayed type IVP in the neutrophil-depleted rabbits. (7) GRO induced a delayed type of IVP via inducing the production of TNFα. Thus, TNFα-induced IL-8 is responsible for the mediation of delayed IVP in LPS-induced pleurisy of rabbits. This mechanism may generally be applicable to many types of acute inflammations, because similar IVP was also observed in inflammations at different site of the body, i.e. articular cavity and vitreal space as well as the inflammation with a different stimuli, i.e. urea crystal in rabbits.