Receptor-directed inhibition of chemotactic factor-induced neutrophil hyperactivity by pyrazolon derivatives. Definition of a chemotactic peptide antagonist.

Abstract

A B S T R A C T The two pyrazolon derivatives, phenylbutazone and sulfinpyrazone, selectively inhibit chemotactic peptide-induced effects on neutrophils. As they antagonize the induction of acute neutropenia in vivo and of cellular hyperadhesiveness, lysosomal enzyme release, hexose monophosphate shunt activity, and superoxide production in vitro, these effects occur with a specificity not shared with other prostaglandin biosynthesis inhibitors. Inhibition by these drugs resembles the competitive type ofantagonism and occurs at concentrations attainable in vivo under clinical conditions. The locomotory machinery, the directionfinding mechanisms, and the basic metabolic machinery ofthe cell are unaffected. These drugs interfere with specific binding of the formylpeptide to its receptor on neutrophils.

Role of Complement-Derived and Bacterial Formylpeptide Chemotactic Factors in the In Vivo Migration of Neutrophils in Experimental Escherichia coli Pyelonephritis in Rats

“…PB treatment was administered in the present study at doses that others have shown to completely prevent the neutropenia induced in rabbits by iv injection of the formylpeptide formyl-methionylleucyl-phenylalanine [12]. Although a different efficacy of this drug in the rat can not be excluded, ratio (table 1).…”

“…Hypocomplementemia was checked by measuring levels of total serum hemolytic complement (CH so ) and immunoreactive C3 and the capacity of the serum to generate in vitro neutrophil migration upon zymosan activation. Second, rats were treated with phenylbutazone (PB), a competitive inhibitor of chemotactic formylpeptides for neutrophil receptors [11][12][13], in doses that prevented formylpeptide-induced neutropenia in rabbits [12]. Some of the animals were killed during the acute phase of pyelonephritis, and the neutrophil infiltration of their kidney parenchyma was determined by measuring the myeloperoxidase (MPO) activity, an enzymatic marker for neutrophil infiltration [1].…”

Effect of indomethacin on the binding of the chemotactic peptide formyl‐Met—Leu—Phe on human polymorphonuclear leukocytes

“…They found that two other anti-inflamrnatory drugs, phenylbutazone and sulfinpyrazone possess in vivo, as well as in vitro, potent antagonistic properties against FMLP-induced PMN alteration in rabbits, and in vitro in human. They found also that both drugs were inhibitors of the binding of [14]. However, this result is not surprising since 100% autologous heat-inactivated plasma was used in the radioligand binding assay [14].…”

“…They found also that both drugs were inhibitors of the binding of [14]. However, this result is not surprising since 100% autologous heat-inactivated plasma was used in the radioligand binding assay [14].…”

Formylated Chemotactic Peptides Can Mimic the Secondary, Provoking Endotoxin Injection in the Generalized Shwartzman Reaction

“…The mechanisms responsible for this phenomenon are presently unknown. Since endotoxin and fMLP possess similar granulocyte activating potencies [3], we suggest that endotoxin-induced endothelial damage may play an essential role: if fMLP-activated, hyperadhesive [4] granulocytes encounter endothelial cells that have been injured by endotoxin (an injury that does not occur with fMLP alone), the result is a deleterious sequence of events (e.g., persistent neutropenia; see table). In contrast, if granulocytes activated by either endotoxin or fMLP encounter native, undamaged endothelium, subsequent alterations remain limited.…”