sue. The current study merely performed a between-groups comparison of steroid-naive ... Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM.
260
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
lished data show that the signal should be linearized and analyzed quantitatively to take maximal advantage of the nasal prongs capabilities. The trend toward progressive quantification has been reinforced by the most recently issued recommendations (3). Improved quantification of flow events will help in standardizing the assessment of respiratory events, thereby minimizing the variability in the detection and classification of respiratory sleep disorders (9). In addition, better quantification of flow recording would facilitate both the detection of inspiratory flow limitation and the study of its clinical impact. As Heitman and coworkers (6) and other authors have stated (10), the detection of respiratory sleep disturbances by using nasal prongs suffers from a potential drawback. The sensor fails in the case of mouth breathing with the result that false apneas can be detected in some patients. This artifact, however, which is characterized by a loss of flow signal, can be easily detected and the erroneous data can be discarded. It should be pointed out that a satisfactory performance of nasal prongs in detecting sleep disturbances does not necessarily mean that this simple device ensures the accurate measurement of patient ventilation throughout the night (4, 5). Because small changes in the placement of the nasal prongs could modify the gain of the pressure–flow relationship (1), the flow assessed by nasal prongs in a given respiratory sleep event must always be compared with the normal flow in the preceding minutes. This check prevents the device from measuring the absolute value of ventilation. However, accurate detection of relative changes in flow amplitude within short time periods is possible. Taken together, the data from Heitman and coworkers (6) and all the previous data evaluating nasal prongs offer strong evidence in support of the use of this simple device in detecting respiratory flow events in routine sleep studies. JOSEP M. MONTSERRAT, M.D. Institut Clínic de Pneumologia i Cirurgia Toràcica Hospital Clínic Barcelona, Spain
VOL 166
2002
RAMÓN FARRÉ, PH.D. Unitat de Biofísica i Bioenginyeria Facultat de Medicina Universitat de Barcelona Barcelona, Spain References 1. Montserrat JM, Farré R, Ballester E, Felez M, Pastó M, Navajas D. Evaluation of nasal prongs for estimating nasal flow. Am J Respir Crit Care Med 1997;155:211–215. 2. Norman RG, Ahmed MM, Walsleben JA, Rapoport DM. Detection of respiratory events during NPSG: nasal cannula/pressure sensor versus thermistor. Sleep 1997;20:1175–1185. 3. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome, definition, and measurement techniques in clinical research. Sleep 1999;22:667–689. 4. Farré R, Rigau J, Montserrat JM, Ballester E, Navajas D. Relevance of linearizing nasal prongs for assessing hypopneas and flow limitation during sleep. Am J Respir Crit Care Med 2001;163:494–497. 5. Thurneer R, Xiaobin X, Block KE. Accuracy of nasal cannula pressure recordings for assessment of ventilation during sleep. Am J Respir Crit Care Med 2001;164:1914–1919. 6. Heitman SJ, Atkar RS, Hajduk EA, Wanner RA, Flemons WW. Validation of nasal pressure for the identification of apneas/hypopneas during sleep. Am J Respir Crit Care Med 2002;166:386–391. 7. Gould GA, Whyte KF, Rhind GB, Airlie MAA, Catterall JR, Shapiro CM, Douglas NJ. The sleep hypopnoea syndrome. Am Rev Respir Dis 1988;137:895–898. 8. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest 1993;104:781–787. 9. Redline S, Kapur VK, Sanders MH, Quan SF, Gottlieb DJ, Rapoport DM, Bonekat WH, Smith PL, Kiley JP, Iber C. Effects of varying approaches for identifying respiratory disturbances on sleep apnea assessment. Am J Respir Crit Care Med 2000;161:369–374. 10. Hernández L, Ballester E, Farre R, Badia JR, Lobelo R, Navajas D, Montserrat JM. Performance of nasal prongs in sleep studies: spectrum of flow-related events. Chest 2001;119:442–450. DOI: 10.1164/rccm.2205020
Transcriptional Machinery in Asthma Closing the Gap with Clinical Phenotypes 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 chro-
matin 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.
261
Editorials
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. PETER J. STERK, M.D., PH.D. Department of Pulmonary Diseases Leiden University Medical Center Leiden, The Netherlands LEO KOENDERMAN, PH.D. Department of Pulmonary Diseases University Medical Center of Utrecht Utrecht, The Netherlands References 1. Busse WW, Lemanske RF. Asthma. N Engl J Med 2001;344:350–362. 2. Berger SL. Gene activation by histone and factor acetyltransferases. Curr Opin Cell Biol 1999;11:336–341. 3. Kuo M-H, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. BioEssays 1998;20:615–626. 4. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 2002;166:392–396. 5. Yao TP, Ku G, Zhou N, Scully R, Livingstone DM. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci USA 1996;93:10626–10631. 6. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms an multimeric activation complex with PCAF and CBP/p300. Cell 1997;90:569–580. 7. Drost EM, Gilmour PS, Ritchie H, Newman W, Barr J, Agius R, Donaldson K, Rahman I, MacNee W. Histone acetylase expression in sputum leukocytes may be associated with cytokine generation in COPD [abstract]. Am J Respir Crit Care Med 2001;163(4 pt 2):A908. 8. Bai S, Cao X. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor- signalling. J Biol Chem 2002;277:4176–4182. 9. Matthews JG, Ito K, Adcock IA, Barnes PJ. Defect in histone acetylation persists in corticosteroid-resistant and corticosteroid-dependent asthma after long-term follow-up [abstract]. Am J Respir Crit Care Med 2001;163(4 pt 2):A439. 10. Szefler SJ, Leung DYM. Glucocorticoid-resistant asthma: pathogenesis and clinical implications for management. Eur Respir J 1997;10:1640–1647. 11. Ito K, Papi A, Casolari P, Ciacci A, Fabbri LM, Barnes PJ. Histone deacetylase expression and activity in COPD [abstract]. Am J Respir Crit Care Med 2002;165(8 pt 2):B5. 12. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress induces histone acetylation in alveolar epithelial cells [abstract]. Am J Respir Crit Care Med 2001;163(4 pt 2):A218. DOI: 10.1164/rccm.2205018
