Effects of non-steroidal anti-inflammatory drugs on isolated human polymorphonuclear leukocytes (PMN): Chemotaxis, superoxide production, degranulation and (FMLP) Receptor Binding

A receptor binding and digestive activity of human polymorphonuclear leukocytes (PMNs) toward formyl-methionyl-leucyl-[3H]phenylalanine (3H- FMLP) was examined with the following results: Up- and down-regulation and recovery of 3H-FMLP binding activity were demonstrated. Both intact PMN and a lysate prepared from them cleaved the carboxyl terminal amino acid (phenylalanine) of 3H-FMLP. The digestive activity decreased as the receptor binding was inhibited by n-ethylmaleimide and 4- chloromercuribenzoate. Little digestive activity was found in the supernatant from PMN stimulated by FMLP. The released phenylalanine was found in the pellet and supernatant of PMNs. Digestive activity with cathepsin A-like characteristics was found in the lysate of PMN. These observations suggest that FMLP is internalized in lysosomes in a receptor-mediated manner and cleaved by the cathepsin A-like enzyme, the free phenylalanine is released extracellularly, and a part of the dissociated receptors with FMLP may return to the surface or to an intracellular receptor pool. Another finding was that the digestive activity of the lysate of cord blood granulocytes was decreased compared with that of adult blood granulocytes. This decrease may explain in part the impaired chemotaxis of cord blood granulocytes.

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Effect of Some Anti-Inflammatory Drugs on Human Neutrophil Chemotaxis

Journal of International Medical Research ◽

10.1177/030006059402200206 ◽

1994 ◽

Vol 22 (2) ◽

pp. 100-106 ◽

Cited By ~ 12

Author(s):

G Hasçelik ◽

B ŞLener ◽

Z Hasçelik

Keyword(s):

Acetylsalicylic Acid ◽

Polymorphonuclear Leukocyte ◽

Polymorphonuclear Leukocytes ◽

Diclofenac Sodium ◽

Tiaprofenic Acid ◽

Boyden Chamber ◽

Random Migration ◽

Leukocyte Chemotaxis ◽

Inflammatory Drugs ◽

Anti Inflammatory

The effects of piroxicam, tenoxicam, diclofenac sodium, acetylsalicylic acid and tiaprofenic acid on the chemotaxis and random migration of human polymorphonuclear leukocytes were investigated, using zymosan-activated serum as chemo-attractant, with a modified Boyden chamber technique. All five compounds significantly reduced chemotaxis. The random migration of polymorphonuclear leukocytes was inhibited by piroxicam, diclofenac sodium and tiaprofenic acid but not by tenoxicam or acetylsalicylic acid. The inhibitory effect of these non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte chemotaxis and on random migration was generally dose-dependent. The results suggest that the drugs studied may have a direct effect on polymorphonuclear leukocyte chemotaxis and that this activity may contribute to their anti-inflammatory properties.

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Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature

Blood ◽

10.1182/blood-2010-02-270520 ◽

2010 ◽

Vol 116 (20) ◽

pp. 4288-4296 ◽

Cited By ~ 49

Author(s):

Magali Pederzoli-Ribeil ◽

Francesco Maione ◽

Dianne Cooper ◽

Adam Al-Kashi ◽

Jesmond Dalli ◽

...

Keyword(s):

Polymorphonuclear Leukocytes ◽

Early Stage ◽

Leukocyte Adhesion ◽

Formyl Peptide Receptor ◽

Annexin A1 ◽

Formyl Peptide ◽

Anti Inflammatory ◽

Human Polymorphonuclear Leukocytes

Abstract Human polymorphonuclear leukocytes adhesion to endothelial cells during the early stage of inflammation leads to cell surface externalization of Annexin A1 (AnxA1), an effector of endogenous anti-inflammation. The antiadhesive properties of AnxA1 become operative to finely tune polymorphonuclear leukocytes transmigration to the site of inflammation. Membrane bound proteinase 3 (PR3) plays a key role in this microenvironment by cleaving the N terminus bioactive domain of AnxA1. In the present study, we generated a PR3-resistant human recombinant AnxA1—named superAnxA1 (SAnxA1)—and tested its in vitro and in vivo properties in comparison to the parental protein. SAnxA1 bound and activated formyl peptide receptor 2 in a similar way as the parental protein, while showing a resistance to cleavage by recombinant PR3. SAnxA1 retained anti-inflammatory activities in the murine inflamed microcirculation (leukocyte adhesion being the readout) and in skin trafficking model. When longer-lasting models of inflammation were applied, SAnxA1 displayed stronger anti-inflammatory effect over time compared with the parental protein. Together these results indicate that AnxA1 cleavage is an important process during neutrophilic inflammation and that controlling the balance between AnxA1/PR3 activities might represent a promising avenue for the discovery of novel therapeutic approaches.

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