Inflammation/inflammatory response inducers

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

There are three major hallmarks of Pb-induced immunotoxicity (1) Pb can dramatically suppress the Thl-dependent DTH response, as well as production of associated Thl cytokines (2) Pb can dramatically elevate production of IgE while increasing production of Th2 cytokines such as IL-4 and (3) Pb can impair the production of new macrophages and shift existing macrophage populations into a hyper-inflammatory response phenotype that promotes tissue inflammation but, ironically, is not particularly effective against bacterial pathogens. 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

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