Mechanism of delayed phase of increased vascular permeabitity in acute inflammation

为探讨急性炎症时血管通透性增加（IVP）的机制，我们研制了重组细胞因子，包括白细胞介素（IL）-1β、肿瘤坏死因子-α（TNFα）、IL-1受体拮抗剂（IL-1a）、IL-8、生长刺激癌基因（GRO）、单核细胞趋化蛋白-1（MCP-1）及其抗体，并建立了免疫分析系统。本实验采用家兔内毒素性胸膜炎模型，在上述材料和方法的基础上，测定了白细胞介素（IL）-8作为急性炎症IVP延迟相的直接介质：（1）再次证实了内毒素性胸膜炎IVP与其他类型急性炎症一样，呈双相性，即时相由组胺介导。(2)用相应的抗体阻断TNFα或IL-8，可使延迟通透性消失，而对即刻通透性的持续时间和强度无影响。IL-1 ra不抑制延迟的IVP。(3)在嗜中性粒细胞耗竭的家兔中未观察到延迟的通透性，但TNFα的产生得以维持。(4)胸膜内注射兔重组TNFα或IL-8可诱导延迟型IVP，抗组胺药对此无抑制作用。(5)注射TNFα可诱导IL-8的产生。(6)IL-8而非TNFα可诱导中性粒细胞耗竭兔的延迟型IVP。(7)GRO通过诱导TNFα的产生诱导延迟型IVP。因此，TNFα诱导的IL-8负责介导LPS诱导的家兔胸膜炎中延迟IVP。这一机制通常适用于许多类型的急性炎症，因为在身体不同部位的炎症（即关节腔和玻璃体间隙）以及不同刺激物（即家兔尿素晶体）的炎症中也观察到类似的IVP。

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.