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The integrin alpha subunits play a major role in the regulation of ligand binding specificity. To gain further insight into the regions of the alpha subunits that regulate ligand specificity, we have utilized alpha v / alpha IIb chimeras to identify regions of alpha IIb that when substituted for the homologous regions of alpha v switched the ligand binding phenotype of alpha v beta 3 to that of alpha IIb beta 3. We report that the ligand recognition specificity of beta 3 integrins is regulated by the amino-terminal one-third of the alpha subunit. Substitution of the amino-terminal portion of alpha v with the corresponding 334 residues of alpha IIb reconstituted reactivity with both alpha IIb beta 3-specific activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies in addition to small highly specific activation-independent ligands. In contrast, substitution of the amino-terminal portion alone or the divalent cation repeats alone were not sufficient to change ligand binding specificity. These data in combination with previous studies demonstrate that integrin ligand recognition requires cooperation between elements in both the alpha and beta subunits and indicate that the ligand binding pocket is a structure assembled from elements of both the alpha and beta subunits.

The metabolic and functional alterations which occur during the acute phase of nephrotoxic nephritis (NTN) in rats, a model of immune-mediated glomerulonephritis, result from a cooperative interaction between PMNs and platelets (PLTs). In consequence, we hypothesized that fibrinogen (Fg) might play a critical role in this process and, accordingly, we found that defibrination of animals decreased both the acute phase proteinuria in NTN (-70%) as well as the influx of PLTs and PMNs into the glomerulus (-40-50%). Invest. 1994. 94:928-936.)

The effects of the newly discovered bicyclic prostaglandin, prostacyclin (PGI2), on the pulmonary and systemic vascular beds were investigated in the anesthetized dog. PGI2 decreased systemic and pulmonary arterial pressures in a dose-related manner when injected into the vena cava in doses of 1--30 microgram. Since left ventricular end-diastolic, left atrial, and right atrial pressures were unchanged, and since cardiac output was increased or unchanged, pulmonary and systemic vascular resistances were decreased. PGI2 was 10 times more potent than prostaglandins E1 or E2 in decreasing aortic pressure when injected intravenously, and the effects of PGI2 on the systemic vascular bed were similar when injected into the vena cava or the left atrium. These data indicate that inactivation of PGI2 is minimal in the lung. The stable prostacyclin metabolite, 6-keto-PGF1alpha, had little hemodynamic effects, suggesting that responses to PGI2 were not due to formation of this metabolite. PGI2 produced dose-dependent increases in blood flow in the mesenteric and renal vascular beds. These data demonstrate that PGI2 has marked vasodilator activity in the pulmonary and systemic vascular beds and suggest that prostacyclin is the only known metabolite of arachidonic acid that dilates the pulmonary and systemic circulations.