NEW YORK (Reuters Health) - Airway smooth-muscle cells in patients with asthma, unlike those of nonasthmatic individuals, do not express the antiproliferative transcription factor C/EBP-alpha, according to a report in The New England Journal of Medicine for August 5th.
This apparently explains the increased proliferation of this tissue in asthmatics, Dr. Michael Roth of the University of Sydney, Australia and associates suggest, as well as the cells’ hyperresponsiveness and the failure of glucocorticoids to inhibit proliferation of these cells.
Because of the importance of glucocorticoid treatment in asthma, Dr. Roth’s group examined the signaling pathway that controls the inhibitory effect of glucocorticoids on cell proliferation in cells from 20 subjects with asthma, 8 subjects with emphysema, and 26 control subjects.
They found that, even though budesonide, dexamethasone, and prednisolone activated the glucocorticoid receptor in bronchial smooth-muscle cells from subjects with and without asthma, the drugs inhibited proliferation only in cells from subjects without asthma.
“We showed that the lack of anti-proliferative action of glucocorticoids in asthma smooth muscle cells is based on the cell-type specific lack of C/EBP-alpha protein expression,” Dr. Roth told Reuters Health.
“While the anti-inflammatory action of glucocorticoids is mainly mediated via the glucocorticoid receptor alone, the anti-proliferative action, in normal cells, involves a complex that is formed by C/EBP-alpha and the glucocorticoid receptor. If one factor is missing the proliferation is not halted.”
When transfected with an expression vector for human C/EBP-alpha, cells from asthma patients did express the protein. Furthermore, transfection with the expression vector slowed the proliferation of the cells in the presence of fetal-calf serum and further reduced proliferation in the presence of budesonide.
“The lack of C/EBP-alpha is cell-type specific since lymphocytes of asthma patients express the protein,” Dr. Roth said.
“A possible new therapeutic approach may therefore be based on the re-activation of the translation of C/EBP-alpha specifically in asthmatic smooth muscle cells,” he continued. “If this would be successful, we may even offer a cure for asthma. Until then, glucocorticoids combined with beta-2-agonists seem to be the best available option.”
Source: N Engl J Med 2004;351:560-574. [ Google search on this article ]
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