Inflammatory cascades

NSAIDs act primarily by inhibiting prostaglandin synthesis, which is only a small portion of the inflammatory cascade. They possess both analgesic and antiinflammatory properties and reduce stiffness but do not slow disease progression or prevent bony erosions or joint deformity. They should seldom be used as monotherapy for RA instead, they should be viewed as adjuncts to DMARD treatment. Common NSAID dosage regimens are shown in Table 4-4. 

Two recently introduced biological therapies were designed to interfere with the inflammatory cascade initiate by TNF-a. Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indicated for therapy of Crohn s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs. 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

In conclusion, the beneficial effects of flavonoids in experimental IBD are mostly related with a preservation of intestinal function and/or with their ability to interfere simultaneously with different steps in the inflammatory cascade i.e. eicosanoid generation, oxygen and nitrogen reactive metabolites production and pro inflammatory cytokine release. The interest of flavonoids as potential drugs in the treatment of IBD is growing, and recently the intestinal antiinflammatory effects of the derivate flavonoid DA-6034 (7-carboxymethyloxy-3, 4, 5-trimethoxy flavone) has been reported in three... 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

Since aiAT represents the archetype for the serpin (serine-proteinase inhibitor) superfamily of proteins, it is possible that similar oxidative or proteolytic mechanisms may function in the inactivation of other serpins that are important in controlling the inflammatory cascade. Some serpins contain a readily oxidised reactive-centre methionine residue (e.g. plasminogen activator-inhibitor [108] and a2-antiplasmin [109]), whilst all serpins (including antithrombin III [110] and protease nexin I [111]) contain an exposed loop which is susceptible to cleavage by proteinases. 

In the first differential proteomics approach for the identification and characterization of proteins involved in both the inflammatory cascade and Leflunomide mode of action (Dax et al, 1998), the murine monocyte/macrophage cell line RAW 264.7 was employed and the RAW 264.7 proteomes of normal, unstimulated RAW 264.7 macrophages with the respective LPS-stimulated and/or drug-treated were compared. This cell line was chosen since RAW 264.7 cells have been used as a model system to study immune responses (Bahl et al, 1994) successfully before. 

Both inflammatory andneurodegenerative components may contribute to the clinical profile of MS. Inflammation appears to be caused by overactive pro-inflammatory T helper 1 cells, initiating the inflammatory cascade. Current IFNp and glat-iramer acetate are most effective in this inflammatory phase of MS. Recent evidence also show s that inflammation may not only be destructive but may also play a part in tissue repair (Grigoriadis et al., 2006). 

Block late reaction to allergen and reduce airway hyperresponsiveness. inhibit production of cytokines responsible for initiation of inflammatory cascade. 

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