Platelets,Prostaglandins,Red Cells,Sedimentation Rates,Serum and Tissue Proteins and Non-Steroidal Anti-Inflammatory Drugs

Abstract

Discussion and Summary

In a circumscribed series of somewhat indirectly interrelated investigations, it has been shown that some substances (hyaluronic acid, chondroitin sulfate, ribonucleic acid, deoxyribonucleic acid and certain enzymes, among others) accelerate erythrocyte sedimentation rates when added or inoculated in vitro and in vivo. It has been shown, too, that some of these same agents; as well as others like digitonin, Filipin, and phospholipase A, cause varying amounts of release or an increase in synthesis of PGF_2a when added to platelets.

Certain of the above reactions (the accelerated ESR and platelet release of PGF_2a) are inhibited by the addition or administration of appropriate anti-inflammatory drugs in vivo and in vitro. Freeze–thawing and soni-cation, as well as addition of calcium and NaF to platelets, also elicits increases in PGF_2a concentrations in the surrounding plasma. This PGF_2a release (presumably synthesis) is inhibited by adding the appropriate anti-inflammatory drugs. LDH release is unaffected.

It appears that the non-enzymic-induced ESR, as well as certain artificially induced platelet PGF_2a release reactions, may be secondary manifestations of primary alterations on cell membranes. They may be interrelated. The two processes are inhibited by similar types of drugs, the platelet reaction being far more sensitive, and they may have significance to initiation and maintenance of inflammatory reactions in animals and man. These ideas gain more merit, perhaps, when it is shown that certain serum proteins of the rat (the alpha- and beta-globulins) increase in response to some types of inflammation, that artificially induced inflammatory reactions in the rat are inhibited by the intravenous administration of these particular rat proteins and that, less importantly perhaps, the same proteins prevent the accelerated ESR in vitro in response to the addition of dextran. Their effects on platelets have not been studied.

It may be surmised, then, that certain serum protein changes in response to tissue damage may be protective, primarily, and that they, like non-steroidal anti-inflammatory drugs, modulate characteristic responses to changes in the cellular environment.

Although observations with red cells, platelets, certain drugs, and tissue or plasma proteins appear logical, pertinent and interrelated, these artificially derived laboratory results may be fortuitous. More work needs doing, for example, in the specific areas of cells and, even more importantly, in the greater general areas of inflammatory disease. The most pressing problem concerns the probable application of these isolated observations to the treatment of man and his diseases—inflammation, vascular disease, transplant complications, and a variety of others in which cell accumulation, aggregation and synthesis-release of tissue reactants like prostaglandins may play important contributory physiologic-pathologic roles.

Perhaps PGF_2α plays a supportive role in inflammation; perhaps not (8). At any rate, it represents a convenient assay method for the assessment of more important facets of cellular release mechanisms, alterations, or distortions, in general, and the action of nonsteroidal anti-inflammatory drugs, specifically. The serum response of this material to drugs like indomethacin occurs rapidly; within one hour, following a single oral dose in the rat, and persists for many hours.

Finally, from these and other studies in our laboratories, it appears that there is no dearth of so-called “mediators” to assure that inflammation will proceed in the almost total absence of any one of them. Perhaps the final role of the prostaglandins and the control of their synthesis, may reside in the area of physiologic homeostasis rather than in that of pathologic phenomena, as reflected by various inflammatory reactions.