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Weissmann G
The biochemistry of inflammation: Rheumatoid arthritis and anti-inflammatory drugs.

Eur J Rheumatol Inflamm, 5(4): 366-381, 1982
ISSN: 0140-1610 European Journal of Rheumatology and Inflammation (PubMed)

Abstract
Rheumatoid arthritis is characterized by joint inflammation: heat, pain, redness, swelling and finally, loss of function. These cardinal signs of inflammation are usually launched in tissues by the interaction of cells of the host with invading bacteria or viruses, or to irritants the nature of which remain unknown. The latter, unfortunately, describes the situation in rheumatoid arthritis. Consequently, rheumatic diseases may be considered diseases of sterile inflammation launched by an unknown invader or a genetic flaw. Lysosomal enzymes and complement are probably the most significant mediators of tissue injury released in the course of inflammatory arthritis. White cells, when stimulated to phagocytose particles such as immune complexes (aggregated IgG and rheumatoid factor) release a series of lytic ferments (lysosomal enzymes). These lysosomal enzymes include proteases capable of cleaving all of the connective tissue substrates present in cartilage or surrounding tissues. The enzymes are capable of degrading collagen, elastin, and the proteoglycans which constitute the bulk of cartilage. Glucocorticoids inhibit release of prostaglandins and thromboxanes in several systems: (1) the isolated, perfused guinea pig lung challenged by antigen or a releasing factor (RCS-RF), (2) blood vessels which release prostacyclin after prolonged vasoconstriction induced by noradrenalin, (3) the perfused cat spleen similarly stimulated with noradrenalin, (4) incubated slices of mesentery from ovalbumin-sensitized guinea pigs exposed to antigen, (5) inflamed ocular tissues which release prostaglandins, (6) dogs or cats suffering from shock sufficient to raise myocardial prostaglandin levels, and (7) human psoriatic skin which contains excessive amounts of HETE. It is now generally appreciated that aspirin and indomethacin inhibit the transformation of arachidonic acid - via appropriate intermediates - to stable prostaglandins (PGE2, PGF(2alpha)), prostacyclin and the thromboxanes by inhibiting cycloxygenase. Other nonsteroidal antiinflammatory substances such as piroxicam, naproxen, and ibuprofen also inhibit prostaglandin biosynthesis by this means. By contrast, steroidal anti-inflammatory drugs do not inhibit the activity of the 'prostaglandin synthetase' system in microsomal fractions. Recent experiments show that cortisol inhibits the formation of prostaglandins and thromboxanes in phagocytosing cells, an end result which resembles that produced by treatment of patients or cells with aspirin. However, there is a significant difference. If one adds exogenous arachidonic acid to aspirintreated aspirin treated or to cells from aspirin-treated patients, one cannot reverse the block of prostaglandin or thromboxane synthesis. This is because aspirin inhibits the cycloxygenase enzymes required to transform arachidonate. In contrast, the addition of exogenous arachidonate overcomes cortisone-induced inhibition of prostaglandin and thromboxane formation, indicating a site of action proximal to the release of arachidonic acid.

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