Pharmacologic manipulation of leukocyte chemotaxis. Present knowledge and future trends.
The chemotactic responses of leukocytes are initiated by the binding of chemoattractants to specific cell-surface receptors. At larger doses, chemoattractants stimulate other biologic activities in leukocytes, including the production of superoxide anions and the secretion of lysosomal enzymes. The tissue-destructive properties of inflammatory cells relate largely to these latter two biologic responses. It has recently been shown that the oligopeptide chemotactic factor receptor in human polymorphonuclear leukocyte membranes exists in high- and low-affinity states that are interconvertible and regulated by guanine nucleotides. In whole polymorphonuclear leukocytes, only one affinity of the receptor can be seen due to rapidly ongoing cellular processes. This affinity can be modified by agents that alter the physical state of the membrane and can be enhanced by aliphatic alcohols, agents that decrease membrane microviscosity. Under these conditions, the chemotactic responsiveness of polymorphonuclear leukocytes is enhanced, but lysosomal enzyme secretion and superoxide anion production are markedly depressed. Polyene antibiotics, which bind membrane cholesterol, decrease the affinity of the receptor. These agents also depress chemotaxis but enhance lysosomal enzyme secretion. These findings indicate that the transduction mechanisms for certain biologic responses initiated by chemoattractant receptors are heterogeneous. The particular transduction pathway initiated by chemotactic factors is reflected by the affinity state of the receptor. The higher affinity initiates chemotaxis whereas the lower affinity initiates lysosomal enzyme secretion and superoxide anion production. These findings suggest that pharmacologic agents may well be developed, which can selectively affect the specific functions of polymorphonuclear leukocytes in man. Anti-inflammatory agents that can decrease leukocyte lysosomal enzyme secretion and superoxide anion production, but not chemotaxis, may well be useful in the treatment of certain rheumatic diseases.
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