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Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Correspondence and requests for reprints should be addressed to Robert P. Schleimer, Ph.D., Northwestern University Feinberg School of Medicine, Division of Allergy-Immunology, 240 East Huron, Room 2318, Chicago, IL 60611. E-mail: rpschleimer{at}northwestern.edu
Dr. Adcock presented evidence that histone deacetylase (HDAC) activity helps control the sensitivity of corticosteroids in repressing the action of nuclear factor (NF)-
B. Asked about the mechanism of the downregulation of HDAC in chronic obstructive pulmonary disease (COPD), Dr. Adcock stated that there is a very rapid decrease in the activity of the enzyme that occurs within 20 or 30 min of oxidative stress. This may be due to nitration of tyrosine residues. For HDAC2, this may be targeted to tyrosine residue 146, which is within the active site of HDAC2. Tyrosine nitration also targets proteins for proteasomal degradation, Dr. Adcock explained, so it may be that, in conjunction with the acute decrease in activity, there is chronic proteasomal degradation of HDAC.
It is not known which residues are acetylated on the glucocorticoid receptor, Dr. Adcock told a questioner. However, his group has shown that an acetylated receptor does not associate well with the p65 subunit of NF-B, and, if it is deacetylated, there seems to be better association.
In response to a question about the effect of smoking on HDAC in patients with COPD, a colleague of Dr. Adcock said the HDAC decrease is greater in patients with COPD who are continuing smokers than in those who are ex-smokers. Dr. Adcock added that, in vitro, cigarette smoke has an acute effect on HDAC activity.
A discussant noted that Dr. Adcock's "most striking" data were found in patients with severe COPD, who are typically on copious amounts of medication. A colleague of Dr. Adcock said that patients were specifically excluded from the study if they were on theophylline or steroids. Dr. Adcock acknowledged, though, that some therapies can affect HDAC activity and/or expression. For example, chronic high-dose dexamethasone treatment in cell lines can induce HDAC2 expression. Dr. Adcock said it is not clear whether that action is mediated by the glucocorticoid response element.
After Dr. Johnson's talk on interactions of corticosteroids with ß-agonists and anticholinergics, a discussant observed that airway smooth muscle does more than contract and cause bronchoconstriction; it also generates inflammatory cytokines. M2- and M3-receptors have been shown to activate NF-B and mitogen-activated protein kinase pathways, the discussant noted, which suggests that steroids and inhaled anticholinergics might have synergistic effects. Dr. Johnson concurred. It has been shown, he said, that ß-agonists and steroids are synergistic in suppressing the release of cytokines and chemokines from human airway smooth muscle, although the effect is cell specific.
A discussant asked whether there is any evidence that one glucocorticoid may differ from another in terms of its ability to synergize with ß-agonists or muscarinics. According to Dr. Johnson, in vitro, similar interactions have clearly been shown with fluticasone, budesonide, beclomethasone dipropionate, and dexamethasone. Now that the geometry of the human glucocorticoid receptor has been mapped, he said, glucocorticoid receptor agonists might be developed that have different ways of interacting with the binding site. For example, in the future, perhaps not all glucocorticoid receptor agonists will have a steroidal structure, and they may behave differently from traditional entities. Some of the newer steroids are already producing surprises, Dr. Johnson pointed out. Mometasone, for example, is highly potent at the glucocorticoid receptor but more potent than progesterone at the progesterone receptor. Ciclesonide is highly potent at the glucocorticoid receptor but more potent than estrogen at the estrogen receptor. A discussant mentioned that recent microarray studies in his laboratory suggest that the pattern of gene regulation by glucocorticoids varies among several different compounds tested.
Dr. Giembycz's talk addressed the possibility that certain dual phosphodiesterase (PDE) inhibitors would offer an improved therapeutic ratio over PDE4 inhibitors alone. A discussant asked about the feasibility of using PDE inhibitors, for example a PDE5 inhibitor, to inhibit the breakdown of cyclic 3'5'-guanosine monophosphate, in terms of the possibility of biologic synergy. According to Dr. Giembycz, PDE5 inhibitors such as zaprinast or sildenafil have little antiinflammatory effect on the cells that have been studied. There is a weak bronchodilator effect from compounds that are known to elevate cyclic 3'5'-guanosine monophosphate, but Dr. Giembycz expressed concern about the vasoactive effects of a PDE5 inhibitor. Nevertheless, he said, a case could be made for adding some bronchodilatation to the anti-inflammatory effect of a PDE4 inhibitor.
Another discussant noted that the vasodilatory effect of PDE5 inhibitors might be beneficial because many patients with COPD develop pulmonary hypertension and questioned Dr. Giembycz's concern about vascular effects. Dr. Giembycz replied that he is concerned about the real systemic effects—not effects on the pulmonary circulation, but the potential for these inhibitors to cause prolonged vasodilatation that may predispose to some forms of arteriopathy. To his knowledge, he said, mesenteric arteriopathy has never been seen in humans using PDE inhibitors, but arteriopathy with a PDE4 inhibitor has been noted in nonhuman primates. Dr. Giembycz called arteriopathy "a major concern."
Dr. Barnes presented data on the ability of theophylline to activate HDAC and reverse steroid resistance induced by oxidative stress. Asked whether his laboratory had evaluated other methylxanthines, Dr. Barnes stated that caffeine has a small effect on HDAC and that aminophylline is effective, but the latter is a theophylline derivative. Thus, the effect on HDAC seems to be specific to theophylline, or at least most pronounced with that agent.
A discussant asked whether theophylline is likely to have the same effect in vivo, where there is continued oxidative stress. Dr. Barnes said theophylline does have an anti-inflammatory effect on its own, but his group speculates that it may be attributable to enhancement by endogenous cortisol. They are planning a clinical trial to compare a steroid arm, a theophylline arm, and a theophylline-plus-steroid arm. Another discussant remarked that histone deacetylation is a general mechanism to control gene expression, and he asked what effects could be expected when manipulating it besides potentiating the effect of a steroid. Dr. Barnes responded that theophylline is not dangerous in terms of cancers, infections, and other theoretical risks of interfering with nuclear mechanisms.
If activation of HDAC occurs only at low concentrations, a discussant asked, why do studies in asthma show that the effect of theophylline over a prolonged period is dose dependent and that theophylline works better when it is titrated up to high doses? Dr. Barnes explained that theophylline is a complicated drug; it is a bronchodilator at higher doses and it also has anti-inflammatory effects, presumably more at lower doses. In asthma, he said, it would provide a combination of these actions. Dr. Barnes added that in a study by his group, adding low-dose theophylline to inhaled steroid gave a better effect on asthma control than doubling the dose of steroid in people who were not controlled on the steroid. The discussant argued that although bronchodilatation improved in that study, it cannot be said that asthma control improved because exacerbations were not evaluated.
Another discussant suggested studying activation of HDAC by theophylline in conditions such as eczema and atopic dermatitis, where no confounding bronchodilator action can occur. Dr. Barnes said his group is engaged in collaborative studies with a rheumatologist to try to explore activation of HDAC in rheumatoid arthritis. He said it is thought to be a general mechanism that applies to all diseases, especially where there is oxidative stress, so it should also apply in inflammatory bowel disease, bronchiectasis, and cystic fibrosis.
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FOOTNOTES |
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(Received in original form June 9, 2005; accepted in final form June 10, 2005)
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