Recent advances in platelet-polymorphonuclear leukocyte interaction

Epidemiological evidence suggests a positive correlation between the number of PMN and the risk of ischemic vascular disease. The observation that act ivated PMN induce platelet activation my provide some biological plausibili ty to the role of PMN in thrombogenesis. Between other PMN products, cathep sin G, a protease released during PMN activation, is a potent platelet agon ist. However, the antiproteinases present in plasma could virtually abolish its activity. Indeed it was shown that, when PMN were stimulated after int eraction with platelets in mixed cell population, P-selectin-mediated plate let-PMN adhesion may result in the formation of a sequestered microenvironm ent in which cathepsin G activity is protected by antiproteases. P-selectin -mediated adhesion was also shown to facilitate the transcellular metabolis m of arachidonic acid, resulting in increased production of both thromboxan e B2 and leukotriene C4. PMN adhesion to activated platelets in mixed cell suspensions subjected to high shear rate can be modeled as an adhesion casc ade involving a P-selectin-dependent recognition step followed by an adhesi on-strengthening interaction mediated by the beta(2)-integrin Mac-1. Moreov er, an intermediate tyrosine-kinase-dependent signal regulating beta(2)-int egrin adhesiveness is required. Indeeed activated platelets express not onl y P-selectin but also different beta(2)-integrin ligands including fibrinog en and ICAM-2. Some of the functional responses elicited by P-selectin on P MN could be prevented by specific antibody to the P-selectin glycoprotein l igand-l, indicating that this adhesive receptor is able to transduce an 'ou tside-in' signal when engaged by the ligand. By using activated platelets, P-selectin-expressing CHO cells and soluble recombinant P-selectin, P-selec tin was shown to trigger protein tyrosine phosphorylation in PMN and the ty rosine kinase-dependent function of Mac-1. In conclusion, adherence of acti vated platelets to PMN may be a key event in the sequence of thrombus forma tion. The recognition of the essential contribution of PMN beta(2)-integrin s in addition to P-selectin in platelet-PMN adhesion provides an additional evidence to the broad range of function and mechanisms in which PMN integr ins are involved and may be potential targets for pha macological intervent ion.