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. CONCLUSION 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.

[1]  J. Bousquet,et al.  Glucocorticoid Receptor α and β in Glucocorticoid Dependent Asthma , 2000 .

[2]  M. Sanak,et al.  Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. , 2000, The European respiratory journal.

[3]  A. Sampson,et al.  Effect of intravenous corticosteroid on ex vivo leukotriene generation by blood leucocytes of normal and asthmatic patients , 1999, Thorax.

[4]  Yogesh K. Dwivedi,et al.  Glucocorticoids Stimulate Inflammatory 5‐Lipoxygenase Gene Expression and Protein Translocation in the Brain , 1999, Journal of neurochemistry.

[5]  J. Choi,et al.  Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. , 1999, American journal of respiratory and critical care medicine.

[6]  J. Bousquet,et al.  Glucocorticoid receptors in bronchial epithelial cells in asthma. , 1998, American journal of respiratory and critical care medicine.

[7]  J. Vane,et al.  Eicosanoids, Aspirin, and Asthma , 1998 .

[8]  J. Bousquet,et al.  THE ROLE OF GLUCOCORTICOIDS IN THE MODULATION OF EICOSANOID METABOLISM IN ASTHMA , 1998 .

[9]  J. Bousquet,et al.  Superoxide anion production by monocytes of corticosteroid-treated asthmatic patients. , 1998, The European respiratory journal.

[10]  S. Wenzel,et al.  Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. , 1997, American journal of respiratory and critical care medicine.

[11]  K. Resch,et al.  The mitogen-induced lysophospholipid:acyl-CoA acyltransferase (LAT) expression in human T-lymphocytes is diminished by hydrocortisone. , 1997, Biochemical and biophysical research communications.

[12]  J. Bousquet,et al.  5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors , 1996, The Journal of experimental medicine.

[13]  G. Lazzerini,et al.  Effects of systemic glucocorticosteroids on peripheral neutrophil functions in asthmatic subjects: an ex vivo study , 1995, Mediators of inflammation.

[14]  J. Bousquet,et al.  5-15-diHETE and lipoxins generated by neutrophils from endogenous arachidonic acid as asthma biomarkers. , 1995, Biochemical and biophysical research communications.

[15]  C. Chavis,et al.  Enhancement of leukotriene A4 biosynthesis in neutrophils from patients with rheumatoid arthritis after a single glucocorticoid dose. , 1995, Biochemical pharmacology.

[16]  B. Make,et al.  Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. , 1995, American journal of respiratory and critical care medicine.

[17]  W. Henderson.  The Role of Leukotrienes in Inflammation , 1994, Annals of Internal Medicine.

[18]  K. Miyakawa,et al.  Plasma levels of leukotriene E4 during clinical course of bronchial asthma and the effect of oral prednisolone. , 1994, Chest.

[19]  J. Davis,et al.  Pulmonary failure and the production of leukotrienes. , 1994, Journal of the American College of Surgeons.

[20]  T. Nevalainen.  Serum phospholipases A2 in inflammatory diseases. , 1993, Clinical chemistry.

[21]  W. Busse,et al.  Steroid-resistant asthma. , 1993, The Journal of allergy and clinical immunology.

[22]  P. Barnes,et al.  Anti-inflammatory therapy for asthma. , 1993, Annual review of medicine.

[23]  A. Sampson,et al.  Enhanced leukotriene synthesis in leukocytes of atopic and asthmatic subjects. , 1992, British journal of clinical pharmacology.

[24]  C. Chavis,et al.  Formation of lipoxins and leukotrienes by human alveolar macrophages incubated with 15(S)-HETE: a model for cellular cooperation between macrophages and airway epithelial cells. , 1992, Eicosanoids.

[25]  C. Chavis,et al.  Arachidonate 5-lipoxygenase metabolism in human neutrophils from patients with asthma: in vitro effect of nedocromil sodium. , 1992, International archives of allergy and immunology.

[26]  M. Gerritsen,et al.  Glucocorticoid-mediated alterations in fluidity of rabbit cardiac muscle microvessel endothelial cell membranes: influences on eicosanoid release. , 1991, Biochimica et biophysica acta.

[27]  J. Oates,et al.  Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Yamamoto,et al.  Effects of hydrocortisone and aminophylline on plasma leukotriene C4 levels in patients during an asthmatic attack. , 1990, Prostaglandins, leukotrienes, and essential fatty acids.

[29]  S. Holgate,et al.  The role of leukotrienes and prostaglandins in asthma: evidence from clinical investigations. , 1990, Advances in prostaglandin, thromboxane, and leukotriene research.

[30]  W. König,et al.  The neutrophil and leukotrienes--role in health and disease. , 1990, Eicosanoids.

[31]  A. Wardlaw,et al.  Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. , 1989, The American review of respiratory disease.

[32]  P. Borgeat.  Biochemistry of the lipoxygenase pathways in neutrophils. , 1989, Canadian journal of physiology and pharmacology.

[33]  S. Peters,et al.  An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. , 1989, The Journal of pharmacology and experimental therapeutics.

[34]  R. Naclerio,et al.  Leukotriene B4 as a mediator of early and late reactions to antigen in humans: the effect of systemic glucocorticoid treatment in vivo. , 1989, The Journal of allergy and clinical immunology.

[35]  J. Vanderhoek,et al.  Role of the 15‐Lipoxygenase in the Immune System a , 1988, Annals of the New York Academy of Sciences.

[36]  D. Nelson,et al.  Corticosteroids stimulate an increase in phospholipase A2 inhibitor in human serum. , 1988, Journal of steroid biochemistry.

[37]  G. Weissmann,et al.  Leukotriene B4 synthesis and metabolism by neutrophils and granule-free cytoplasts. , 1986, The Biochemical journal.

[38]  J. Gallin,et al.  Rapid method for isolation of normal human peripheral blood eosinophils on discontinuous Percoll gradients and comparison with neutrophils , 1985 .

[39]  D. Nelson.  Corticosteroid-induced changes in phospholipid membranes as mediators of their action. , 1980, Endocrine reviews.

[40]  B. Samuelsson,et al.  Arachidonic acid metabolism in polymorphonuclear leukocytes: effects of ionophore A23187. , 1979, Proceedings of the National Academy of Sciences of the United States of America.