Effects of glucocorticoids on endogenous and transcellular metabolism of eicosanoids in asthma.
BACKGROUND
Human blood polymorphonuclear cells, which biosynthesize eicosanoids from the 5-lipoxygenase (5-LO) pathway, are likely to be involved in asthma, in which glucocorticoids represent the first line of therapy. Their effects on leukotriene release after a short course of treatment, which have been reported in several studies, are controversial.


OBJECTIVE
We sought to investigate whether long-term oral glucocorticoids inhibit lipid mediators from the 5-LO pathway.


METHODS
Twelve normal control subjects, 29 asthmatic subjects, and 50 glucocorticoid-dependent asthmatic subjects were included in the study. Polymorphonuclear cells were studied for endogenous and transcellular metabolism of eicosanoids.


RESULTS
Total leukotriene B(4) production was significantly lower in cells from glucocorticoid-dependent asthmatic subjects (mean +/- SD, 177 +/- 26 ng/10(7) cells) than in control subjects (406 +/- 27), untreated asthmatic subjects (421 +/- 34), and asthmatic subjects treated with inhaled glucocorticoids (290 +/- 56). When incubated with arachidonic acid, these polymorphonuclear cells released very low amounts of 5(S)- and 12(S)-hydroxy-eicosatetraenoic acid (HETE), whereas endogenous 15(S)-HETE was found in substantial amounts. The transformation of exogenous 15(S)-HETE into 5(S),15(S)-diHETE and lipoxins was significantly more important in untreated asthmatic subjects than in control subjects and glucocorticoid-dependent asthmatic subjects.


CONCLUSIONS
This study showed that long-term oral corticotherapy affects the 5-LO activity and leads to a decrease production of all metabolites in contrast to short-term or inhaled glucocorticoids. This study also questions the site of action of glucocorticoids in regulating the availability of arachidonic acid and potential eicosanoid regulation, as previously held in phospholipase A2 studies.
Vachier
I
I
Clinique des Maladies Respiratoires, CHU-Montpellier INSERM U454, Hôpital Arnaud de Villeneuve, Montpellier, France.
Chavis
C
C
Majori
M
M
Farce
M
M
Bousquet
J
J
Godard
P
P
Chanez
P
P
D058927:5-Lipoxygenase-Activating Proteins; D000280:Administration, Inhalation; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism*; D001507:Beclomethasone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D015777:Eicosanoids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008775:Methylprednisolone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000068299:Salmeterol Xinafoate; D013806:Theophylline / Q000008:administration & dosage / Q000627:therapeutic use
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000319:Adrenergic beta-Antagonists; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D002352:Carrier Proteins; D015777:Eicosanoids; D007476:Ionophores; D008563:Membrane Lipids; D008565:Membrane Proteins; D010743:Phospholipids; D000001:Calcimycin; D000068299:Salmeterol Xinafoate; D013806:Theophylline; D001094:Arachidonate 5-Lipoxygenase; D001507:Beclomethasone; D000420:Albuterol; D002118:Calcium; D011241:Prednisone; D008775:Methylprednisolone