Anti-inflammatory, membrane-stabilizing interactions of salmeterol with human neutrophils in vitro.
1. We have investigated the effects of salmeterol (0.3-50 microM) on several pro-inflammatory activities of human neutrophils in vitro. 2. Oxidant production by FMLP- and calcium ionophore (A23187)-activated neutrophils was particularly sensitive to inhibition by low concentrations (0.3-3 microM) of salmeterol, while the responses of phorbol myristate acetate- and opsonised zymosan-stimulated cells were affected only by higher concentrations (3-50 microM) of the drug. At these concentrations salmeterol is not cytotoxic, nor does it act as a scavenger of superoxide. 3. These anti-oxidative interactions of salmeterol with neutrophils were insensitive to propranolol but could be eliminated by washing the cells, or by pretreatment with low concentrations (1-2 microM) of the pro-oxidative, membrane-destabilizing phospholipids, lysophosphatidylcholine (LPC), platelet activating factor (PAF) and lysoPAF (LPAF). 4. At concentrations of 6.25-50 microM salmeterol interfered with several other activities of stimulated neutrophils, including intracellular calcium fluxes, phospholipase A2 activity and synthesis of PAF. 5. In an assay of membrane-stabilizing activity, salmeterol (25 and 50 microM) neutralized the haemolytic action of LPC, PAF and LPAF. 6. Of the other commonly used beta 2-adrenoceptor agonists, fenoterol, and formoterol, but not salbutamol, caused moderate inhibition of neutrophil oxidant generation by a superoxide-scavenging mechanism. However, unlike salmeterol, these agents possessed only weak membrane stabilizing properties. 7. We conclude that salmeterol antagonizes the pro-inflammatory, pro-oxidative activity of several bioactive lipids implicated in the pathogenesis of bronchial asthma, by a mechanism related to the membrane-stabilizing, rather than to the beta 2-agonist properties of this agent.
Anderson
R
R
Department of Immunology, University of Pretoria, South Africa.
Feldman
C
C
Theron
A J
AJ
Ramafi
G
G
Cole
P J
PJ
Wilson
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D013481:Superoxides / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D004983:Ethanolamines; D010972:Platelet Activating Factor; D013481:Superoxides; D005280:Fenoterol; D000068299:Salmeterol Xinafoate; D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D000420:Albuterol; D002118:Calcium; D000068759:Formoterol Fumarate