PT  - JOURNAL ARTICLE
AU  - Jeffrey R. Jackson
AU  - Brian Bolognese
AU  - Leonard Hillegass
AU  - Shouki Kassis
AU  - Jerry Adams
AU  - Don E. Griswold
AU  - James D. Winkler
TI  - Pharmacological Effects of SB 220025, a Selective Inhibitor of P38 Mitogen-Activated Protein Kinase, in Angiogenesis and Chronic Inflammatory Disease Models
DP  - 1998 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 687--692
VI  - 284
IP  - 2
4099  - http://jpet.aspetjournals.org/content/284/2/687.short
4100  - http://jpet.aspetjournals.org/content/284/2/687.full
SO  - J Pharmacol Exp Ther1998 Feb 01; 284
AB  - Chronic inflammatory diseases often are accompanied by intense angiogenesis, supporting the destructive proliferation of inflammatory tissues. A model of inflammatory angiogenesis is the murine air pouch granuloma, which has a hyperangiogenic component. In this model, we explored the regulation of inflammatory angiogenesis using SB 220025, a specific inhibitor of human p38 mitogen-activated protein (MAP) kinase, with an IC50 value of 60 nM and 50- to 1000-fold selectivity vs. other kinases tested. In vivo, this compound reduced the lipopolysaccharide-induced 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-1β and tumor necrosis factor-α during the chronic inflammatory phase when intense 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 angiogenesis by ≈40%. To further study the effects of p38/CSBP MAP kinase inhibition in angiogenesis-dependent chronic inflammatory disease, SB 220025 was tested in murine collagen-induced arthritis. In this model, SB 220025 was able to prevent the progression of established arthritis. Thus, this p38/CSBP MAP kinase inhibitor, which can reduce inflammatory cytokine production and inhibit angiogenesis, is an effective treatment for chronic proliferative inflammatory disease. The American Society for Pharmacology and Experimental Therapeutics