title: Recent advances in platelet-polymorphonuclear leukocyte interaction.
abstract: Epidemiological evidence suggests a positive correlation between the number of PMN and the risk of ischemic vascular disease. The observation that activated PMN induce platelet activation my provide some biological plausibility to the role of PMN in thrombogenesis. Between other PMN products, cathepsin G, a protease released during PMN activation, is a potent platelet agonist. However, the antiproteinases present in plasma could virtually abolish its activity. Indeed it was shown that, when PMN were stimulated after interaction with platelets in mixed cell population, P-selectin-mediated platelet-PMN adhesion may result in the formation of a sequestered microenvironment in which cathepsin G activity is protected by antiproteases. P-selectin-mediated adhesion was also shown to facilitate the transcellular metabolism of arachidonic acid, resulting in increased production of both thromboxane B2 and leukotriene C4. PMN adhesion to activated platelets in mixed cell suspensions subjected to high shear rate can be modeled as an adhesion cascade involving a P-selectin-dependent recognition step followed by an adhesion-strengthening interaction mediated by the beta(2)-integrin Mac-1. Moreover, an intermediate tyrosine-kinase-dependent signal regulating beta(2)-integrin adhesiveness is required. Indeeed activated platelets express not only P-selectin but also different beta(2)-integrin ligands including fibrinogen and ICAM-2. Some of the functional responses elicited by P-selectin on PMN could be prevented by specific antibody to the P-selectin glycoprotein ligand-1, indicating that this adhesive receptor is able to transduce an 'outside-in' signal when engaged by the ligand. By using activated platelets, P-selectin-expressing CHO cells and soluble recombinant P-selectin, P-selectin was shown to trigger protein tyrosine phosphorylation in PMN and the tyrosine kinase-dependent function of Mac-1. In conclusion, adherence of activated platelets to PMN may be a key event in the sequence of thrombus formation. The recognition of the essential contribution of PMN beta(2)-integrins in addition to P-selectin in platelet-PMN adhesion provides an additional evidence to the broad range of function and mechanisms in which PMN integrins are involved and may be potential targets for pharmacological intervention.
authors.affiliation: Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy. degaetano@cmns.mnegri.it
authors.forename: G
authors.initials: G
authors.lastname: de Gaetano
authors.forename: C
authors.initials: C
authors.lastname: Cerletti
authors.forename: V
authors.initials: V
authors.lastname: Evangelista
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000097:blood; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000166:cytology*; D018821:CD18 Antigens / Q000097:blood; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology; D002450:Cell Communication; D015777:Eicosanoids / Q000097:blood; D006801:Humans; D007511:Ischemia / Q000097:blood; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology; D019007:P-Selectin / Q000502:physiology; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D012697:Serine Endopeptidases; D015398:Signal Transduction; D019851:Thrombophilia / Q000097:blood
chemical_list: D001095:Arachidonic Acids; D018821:CD18 Antigens; D015777:Eicosanoids; D019007:P-Selectin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G