Pharmacological implications in the switch from acute to chronic inflammation
- 34 Downloads
Resolution or persistence of the inflammatory response strictly reflects the dynamic balance between two major determinants: (1) the recruitment of circulating inflammatory cells together with the proliferation of resident cells and (2) the death, or apoptosis, of cells accumulated locally. The link between these two determinants seems to be represented by the incapacity of monocytes and macrophages to switch off activation of inflammation, thereby acting as a major promoter of the inappropriate recruitment, retention and survival of activated cells at inflamed tissue sites. Various pathways contribute to the persistent macrophage activation and, therefore, represent major rational targets for biologic approaches aimed at controlling the evolution of inflammation. These pathways include the continuous recruitment of Th1 cells into inflamed tissues, the subnormal production of anti-inflammatory IL-10 by regulatory T cells and macrophages, the reduced release of adenosine by endothelial cells and fibroblasts, the reduced production of soluble decoy receptors for TNF by macrophages and the reduced local availability of the anti-inflammatory cytokine IL-1 receptor antagonist. Moreover, the persistent activation and the survival of inflammatory cells strictly depends on the activity of the NF-κB system, which is responsible for inducing the synthesis of proinflammatory mediators in inflammatory cells such as monocytes, macrophages, fibroblasts and endothelial cells. It is of note that the activity of the NF-κB system can be inhibited by several drugs such as corticosteroids, leflunomide, cyclosporin A, tacrolimus, high concentrations of sulphasalazine and aspirin, and concentrations of oxaprozin achievable in vivo. Consequently, the possibility of controlling the NF-κB system pharmacologically raises opportunities for developing approaches to interfere with the transformation of transient to persistent inflammatory responses.
Unable to display preview. Download preview PDF.
- Arend, W. P. (2001). Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Sem. Arthritis Rheum. 30, 1–6.Google Scholar
- Baracchini, A., Minisola, G., Amicosante, G., et al. (2001). Oxaprozin: a NSAID able to inhibit the matrix metallo-proteinase activity, Inflammopharmacology 9, 143–146.Google Scholar
- Bevilacqua, M. (2000). Pharmacology of oxaprozin: novel findings, in: Oxaprozin and the daily management of osteomuscolar impairment in arthritic patients, Highlights from the Satellite Symposium on Oxaprozin at the XIV EULAR Congress, pp. 3–6. Adis International, Milan, Italy.Google Scholar
- Bevilacqua, M. (2002). Oxaprozin, a derivative of 2-arylpropionic acid, inhibits nuclear factor-kB at therapeuticallyrelevant concentrations, Ann. Rheum. Dis. 61 (Suppl. 1), p. 355, Abstract n. 18.Google Scholar
- Colville-Nash, P. R. and Gilroy, D. W. (2000). COX-2 and the cyclopentenone prostaglandins — a new chapter in the book of inflammation?, Prost. Lipid Mediators 62, 33–43.Google Scholar
- Ottonello, L., Cutolo, M., Frumento, G., et al. (2002). Synovialfluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and pro-inflammatory cytokines, Rheuma-tology (in press).Google Scholar