|Budget Amount *help
¥12,100,000 (Direct Cost : ¥12,100,000)
Fiscal Year 2000 : ¥3,300,000 (Direct Cost : ¥3,300,000)
Fiscal Year 1999 : ¥2,800,000 (Direct Cost : ¥2,800,000)
Fiscal Year 1998 : ¥2,800,000 (Direct Cost : ¥2,800,000)
Fiscal Year 1997 : ¥3,200,000 (Direct Cost : ¥3,200,000)
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.