Development of anti-chemokine therapies and their application to the treatment of imflammatory lung diseases

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To determine the pathogenic roles of chemokines, especially interleukin-8 (IL-8), and to assess a novel therapeutic approach to inflammatory lung diseases, we developed two anti-chemokine therapies and examined their effects in vivo and in vitro. Ferst, we prepared anti-rabbit IL-8 monoclonal antibody and, to study its in vivo effect, we developed a rabbit model of acute respiratory distress syndrome (ARDS). In this model, reexpansion of the collapsed lung induced ARDS-like lung injury, which was associated with locally augmented production of IL-8. Furthermore, pretreatment with anti-IL-8 antibody significantly attenuated lung injury in this model. Since pretreatment with control IgG did not attenuate the lung injury, we concluded that the protective effect of the IL-8 antibody was attributable to its specific neutralizing effect of IL-8. This result also encourage us to proceed the development of anti-IL-8 antibody as a drug fpr various inflammatory lung diseases. We also designed and produced several antisense S-oligos and second generation oligos for IL-8 and examined their effects on the endotoxin-stimulated IL-8 production in MonoMac6 cells. However, none of them did significantly inhibit IL-8 production. This negative results may come from low DNA uptake by monocytic ccells or from the inappropriate three dimensional structure of these oligos. Since artificial additions to antisense DNA molecules occasionally induce nonspecific stimulation of the cells, it is possible to speculate that this nonspecific activation canceled the sequence-specific inhibitory effect of these oligos. With regard to antisense oligos, we concluded that it is necessary to introduce new method for the efficient uptake of oligo DNAs by the cells and to develop new oligos, which efficiently and specifically inhibit mRNA transcription for a certain time.