Inflammatory Angiogenic Factors in a Model of Chronic Inflammation
In many diseases, there is an apparent co-dependence of inflammation and angiogenesis. There’s a very strong inflammatory component in rheumatoid arthritis, psoriasis, inflammatory bowel disease, during tumor growth and in some angiogenic ocular disorders. Many of the mediators that we think about in inflammation can promote angiogenesis, such as some interleukins, TNFa, prostaglandins, arachidonic acid metabolites and platelet-activating factor. Some of these appear to act indirectly by changing the balance between angiogenesis stimulation and inhibition, promoting the production of some of the more directly acting angiogenesis inducers, such as VEGF.
We have been using an animal model to study angiogenesis in an inflammatory setting, an air pouch granuloma model, in which there is an inflammatory response and the formation of granulomatous tissue. We have assessed the characteristics of this granuloma over time, it’s weight, histological structure, vascular volume, cellularity and mediators produced. Many of these characteristics change during time after the start of granuloma growth.
We have characterized a number of different classes of compounds in this model. Protamine and the angiostatic steroid medroxyprogesterone each blocked about fifty percent of the angiogenesis produced by adjuvant and croton oil injection. SB 203347, an inhibitor of class II, fourteen kDa PLA2, an enzyme thought to be responsible for the production of leukotrienes and platelet-activating factor, produced a striking reduction in the angiogenic response in mice. Inhibitors of p38 MAP kinase were also found to cause a dose-related inhibition of the angiogenic response. These compounds block the production of cytokines, such as TNFa and IL lb.
Thus, in this model of inflammatory angiogenesis, inhibitors of inflammatory mediator production block angiogenesis, possibly by tipping the balance against the production of pro-angiogenic mediators.
KeywordsVascular Endothelial Growth Factor Angiogenic Response Vascular Index Psoriatic Keratinocytes Inflammatory Angiogenesis
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