PHARMACOLOGICAL EFFECTS OF SB-220025, A SELECTIVE INHIBITOR OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE, IN ANGIOGENESIS AND CHRONIC INFLAMMATORY DISEASE-MODELS

Chronic inflammatory diseases often are accompanied by intense angioge nesis, supporting the destructive proliferation of inflammatory tissue s. A model of inflammatory angiogenesis is the murine air pouch granul oma, which has a hyperangiogenic component. In this model, we explored the regulation of inflammatory angiogenesis using SB 220025, a specif ic inhibitor of human p38 mitogen-activated protein (MAP) kinase, with an IC50 value of 60 nM and 50- to 1000-fold selectivity vs. other kin ases tested. In vivo, this compound reduced the lipopolysaccharide-ind uced production of tumor necrosis factor at an ED50 value of 7.5 mg/kg . In the inflammatory angiogenesis model, over the course of granuloma development, we observed elevated levels of interleukin-1 beta and tu mor necrosis factor-alpha during the chronic inflammatory phase when i ntense angiogenesis occurs. SB 220025 at 30 mg/kg b.i.d, p.o. was able to greatly reduce the expression of these cytokines and inhibit angio genesis by approximate to 40%. To further study the effects of p38/CSB P MAP kinase inhibition in angiogenesis-dependent chronic inflammatory disease, SB 220025 was tested in murine collagen-induced arthritis. I n this model, SB 220025 was able to prevent the progression of establi shed arthritis. Thus, this p38/CSBP MAP kinase inhibitor, which can re duce inflammatory cytokine production and inhibit angiogenesis, is an effective treatment for chronic proliferative inflammatory disease.