THE PRESENT KNOWLEDGE OF THE INFLAMMATORY PROCESS AND THE INFLAMMATORY MEDIATORS

Endothelial damage, synovial oedema, Fibrin deposition, polymorphonuclear cell (PMN) invasion, and mild lining cell hyperplasia characterize acute inflammatory arthritis. Later on, perivascular tissue is infiltrated by mononuclear cells. The early events al e mediated by interactions between PMNs and endothelial cells. Both parts in the adhesion event are activated with multiple stimuli resulting in complex interactions of varying intensity and duration. Adhesion molecules present on the surface of PMNs (L-selectin) or induced by inflammatory stimuli (beta(2)-integrins) mediate PMN adhesion to activated endothelium, which has counter receptors (E-selectin for L-selectin and ICAM-1 and ICAM-2 for beta(2)-integrins). At the initial phase L-selectin initiates the rolling of PMNs on endothelial cells. Further stimuli result in a more prolonged adhesion between PMNs and endothelium. At the side of endothelium, induction of P-selectin and PAF by histamine, thrombin and LTC(4) contribute to the acute rolling of PMNs on endothelial surface. Tumor necrosis factor (TNF), interleukin-1 (IL-1) and lipopolysaccharide activate endothelial cells to synthesize interleukin-8 (IL-8), a potent chemotactic and proadhesive mediator for PMNs, and further adhesion molecule (E-selectin), a mediator of long-term adhesion between PMN and endothelium. After adhesion and migration to the focus of inflammation, PMNs induce inflammation by aggregating, releasing hydrolyzing enzymes, generating lipid peroxidation products such as prostaglandins and LTB(4), and oxygen derived free radicals. In studies on the pathogenesis of seronegative spondyloarthropathies, we have shown persistently aberrant PMN function evidenced by enhanced chemotaxis and high production of toxic oxygen derived free radicals by PMN, in the development of chronic inflammation, these aberrations may play a role. Lipopolysaccharide, shown to persist in such patients, could act as a priming factor. The triggering factor(s) and factors contributing to the chronic inflammation in rheumatoid arthritis are not known. In chronic diseases, synovial inflammation is characterized by monocyte/macrophage products such as IL-1, TNF, interleukin-6 (IL-6), IL-8, colony-stimulating Factors, lysosomal enzymes PGE(2), LTB(4), and oxygen derived free radicals. However, in the acute phase or during flare-up of chronic diseases, PMNs contribute to the inflammation by ingesting rheumatoid factors and immune complexes and by producing oxygen derived free radicals. During the first 1-2 years of rheumatoid arthritis, a low response to chemotactic stimuli and low production of oxygen radicals by peripheral blood PMNs seem to be associated with benign disease and a lack of early destruction of joints measured by the presence of radiological erosions.