© 2002 American Thoracic Society
Transcriptional Machinery in AsthmaClosing the Gap with Clinical Phenotypes
a Department of Pulmonary Diseases Leiden University Medical Center Leiden, The Netherlands The current management of asthma is based on targeting airway inflammation, because there is strong evidence that inflammatory mechanisms are responsible for the clinical characteristics of the disease (1). Nevertheless, such therapeutic strategy is largely an empirical approach, since the pathogenesis of airway inflammation in asthma is not well understood. The inflammatory activity of resident cells and infiltrative cells along the tracheobronchial tree seems to be consistent with the hypothesis that localized changes in gene expression are driving the inflammatory cascades in this disease. Therefore, disturbed transcriptional regulation of gene expression is a likely candidate mechanism in the pathogenesis of asthma. The DNA of our chromosomes is tightly folded in complex with histone proteins, forming so-called nucleosomes in a chromatin structure. Initiation of gene transcription is strongly inhibited on such a nucleosomal template (2). Gene transcription requires restructuring of chromatin with nucleosomal unfolding, leading to a more open access to the DNA. This can be achieved by acetylation of aminoterminal extensions of core histones by a family of enzymes: the histone acetyltransferases (HATs). Conversely, histone deacetylases (HDACs) appear to repress gene activation by reestablishing the chromatin structure and by interacting with the transcriptional machinery directly. Interestingly, several transcription factors exhibit endogenous HAT activity, which facilitates their action in promoting gene transcription (3). Hence, proinflammatory activity within the airways in asthma might be regulated by local changes favoring a predominance of HATs to HDACs activity. Such disturbed HAT/HDAC balance could either be a primary defect or just a reflection of mitogenic stimulation in tissue repair areas. In this issue of AJRCCM, Ito and coworkers (4) (pp. 392–396) postulate that balanced inflammatory gene regulation by HATs and HDACs in bronchial tissue of patients with atopic asthma is disturbed toward histone hyperacetylation and thereby enhanced gene transcription. They addressed this by examining the localization (immunohistochemistry), expression (Western blots), and activity (incorporation and release of radiolabeled acetic acid) of a number of members of the HATs and HDACs families in bronchial biopsy specimens of carefully defined patients with atopic asthma and nonatopic control subjects. As a secondary aim they examined whether any such abnormalities still occurred in patients with asthma already receiving inhaled steroid therapy. The results appear to be fairly consistent. Even though bronchial tissue of steroid-naive patients with atopic asthma demonstrated similar bronchial expression of two types of HATs (p300/cyclic-adenosine monophosphate response-element-binding-protein-binding-protein [p300/CBP] and p300/CBP-associated factor [PCAF]) as compared with nonatopic control tissue, it exhibited elevated HATs activity together with reduced HDACs expression and activity (4). Interestingly, such differences were not observed in patients with asthma on relatively low doses of inhaled steroids. These findings are consistent with histone hyperacetylation in asthma, which is not observed in adequately treated patients. Has this any relevance for clinical asthma? The authors provide circumstantial evidence that it does: they demonstrate a relatively strong association between HDACs activity within the airways and FEV1 among the patients with asthma. The lower the HDACs activity, the lower the FEV1. One may wonder whether similar associations would exist with other clinical markers, such as the degree of reversibility in airways obstruction, exacerbation rate, or atopic status. This is only the beginning of an unfolding story. First, there are other types of HATs, such as steroid receptor coactivator-1 (SRC-1) and activator of thyroid and retinoic acid receptors (ACTR), which have been described as steroid receptor cofactors (5). Interestingly, these other HATs interact with PCAF as well as p300/CBP (6) and should therefore be included in future studies. Second, one would expect an association of HATs/HDACs activity with cellular and molecular markers of inflammation in the bronchial wall. This requires in situ HAT/HDAC activity assays and quantitative immunohistochemistry. Epithelial cells demonstrated the most intense expression of these enzymes both in asthma and controls, thereby suggesting that these cells are responsible for the observed differences in HATs and HDACs activity between patients with asthma and normal subjects. The possibility that infiltrative cells are contributing as well, as has been observed in chronic obstructive pulmonary disease (7), cannot, however, be excluded. The current study does not directly examine the effect of steroids or endogenously expressed cytokines on HATs and HDACs expression and activity in asthma. These effects are of interest, not only because several HATs can act as steroid receptor cofactors (5), but also because the HAT/HDAC system is clearly controlled posttranslationally (8). Hence, differences in HATs and/or HDACs activity may also occur at the level of modulating factors in the local milieu of inflamed tissue. The current study merely performed a between-groups comparison of steroid-naive and steroid-using asthmatics. This may have introduced bias and needs to be addressed in randomized, controlled trials. These will also show whether any variability in inflammatory gene regulation is associated with variability in clinical markers. Is unbalanced HAT/HDAC activity associated with uncontrolled or exacerbating asthma? And could it be predictive of steroid-resistant asthma? The same authors recently provided evidence of a persistent defect in histone acetylation in peripheral blood mononuclear cells from steroid-resistant and steroid-dependent patients with asthma (9). This finding suggests that, among the other potential mechanisms (10), poor response to steroids in asthma (and chronic obstructive pulmonary disease) (7, 11) can be related to disturbed HATs/HDACs activity. What are the implications of this for our understanding of asthma pathogenesis and the development of treatment? First, it should be evaluated whether the imbalance in HATs/HDACs activity is a primary defect or whether it results from posttranslational modification induced by growth factors and cytokines. There are probably several inducers of increased histone acetylation, one of them being oxidative stress (12). This question will reinforce research interest in the environmental factors potentially contributing to the pathogenesis of distinct clinical phenotypes of asthma (and chronic obstructive pulmonary disease). If dysbalanced HATs/HDACs activity turns out to be a primary abnormality of gene regulation in asthma, it will stimulate the development of novel intervention strategies. Together with targeting specific transcription factors and posttranscriptional processes, DNA site-specific inhibition of histone hyperacetylation may provide tools for suppressing well-defined inflammatory pathways as opposed to the indiscriminate and, occasionally, not fully effective transcription repression by steroids. However, chromatin remodeling represents the very basis of gene transcription in all cells. Finding specific blockers that interfere exclusively with the putative, aberrant gene control in the airways in asthma might prove a heroic task. REFERENCES
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