Pharmacological Effects of SB 220025, a Selective Inhibitor of P38 Mitogen-Activated Protein Kinase, in Angiogenesis and Chronic Inflammatory Disease Models

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 284; no. 2; pp. 687 - 692
• Main Authors: Jackson, J R, Bolognese, B, Hillegass, L, Kassis, S, Adams, J, Griswold, D E, Winkler, J D
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.1998
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Chronic Disease; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Granuloma - pathology; Imidazoles - pharmacology; Inflammation - physiopathology; Interleukin-1 - biosynthesis; Lipopolysaccharides; Mice; Mitogen-Activated Protein Kinases; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; p38 Mitogen-Activated Protein Kinases; Pyrimidines - pharmacology; Time Factors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-3565; 1521-0103

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 IC 50 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 ED 50 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.