To the Editor: In their study, Ito and colleagues (May 12 issue)1observed reductions in both the activity and expression of histonedeacetylases (HDACs), especially HDAC2, in patients with chronicobstructive pulmonary disease (COPD). In addition, the activityinversely correlated with the severity of COPD.
Histone-modifying enzymes play essential roles in gene regulation.2The balance between histone acetylation and deacetylation appearsto be crucial to normal cell growth. Disruption of either ofthese molecular mechanisms has been associated with the developmentof cancer. Several molecules and genes have been identifiedor developed or both to inhibit HDACs.3 Valproic acid, an antiepilepticdrug that has been commercially available for decades, has beenfound to inhibit HDACs, including HDAC2.4 However, there isno evidence that valproic acid worsens pulmonary function inpatients taking the medicine.5 The "chicken-and-egg" conundrumremains unresolved: Does the reduction of HDAC activity causesevere COPD, or is it a secondary event?
Albert Y. Lin, M.D., M.P.H. Santa Clara Valley Medical Center San Jose, CA 95128 albert.lin{at}hhs.co.santa-clara.ca.us
References
Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352:1967-1976. [Free Full Text]
Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999;98:285-294. [CrossRef][Web of Science][Medline]
Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res 2004;91:137-168. [CrossRef][Web of Science][Medline]
Kramer OH, Zhu P, Ostendorff HP, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 2003;22:3411-3420. [CrossRef][Web of Science][Medline]
Physicians' desk reference. 58th ed. Montvale, N.J.: Thomson PDR, 2004.
To the Editor: The following statement in the Discussion sectionof the article by Ito et al. is rather confusing: "In the presentstudy, there was a positive correlation between HDAC activityand disease severity, as measured by the percent of predictedFEV1 [forced expiratory volume in one second]. . . ." The Resultssection, Figure 1D, and the abstract clearly indicate that therewas apparently a negative correlation between HDAC activityand disease severity. I assume that the authors meant to saythat there was a positive correlation between HDAC activityand FEV1.
Angshu Bhowmik, M.B., B.S. Homerton University Hospital London E9 6SR, United Kingdom
The authors reply: Histone modification regulates many genes,including those involved in normal cell growth. Eleven classicHDACs have been identified.1 In patients with COPD, we founda marked reduction in HDAC2, with lesser reductions in HDAC5and HDAC8. Different HDACs appear to be involved in differentcellular functions and presumably regulate different sets ofgenes. Indeed, the targeted reduction of HDAC2 through RNA interferenceresults in reduced responsiveness to corticosteroids in a humanepithelial cell line (A549), whereas this reduction is not observedwhen other classic HDACs are inhibited.2 Valproate, a nonselectiveinhibitor of classic HDACs, is associated with 50 percent inhibitionof HDAC activity at approximately 200 µg per milliliter(1.4 mmol per liter) in A549 cells. Steady-state plasma concentrationsof valproate in patients with epilepsy are 50 to 100 µgper milliliter (0.3 to 0.7 mmol per liter), so it is possiblethat clinical doses may have some HDAC inhibitory effect, enhancinginflammation or reducing responsiveness to corticosteroids inpatients with inflammatory diseases. There is one report ofincreased circulating proinflammatory cytokines in childrenwith epilepsy treated with valproic acid.3 However, we are notaware that a worsening of inflammatory diseases has been investigatedor reported with valproate. We agree with Dr. Lin that it isnot certain whether the reduction in HDAC activity is a consequenceor a cause of severe COPD, but we would like to suggest thatit is both and that it provides a molecular basis for the increasingpulmonary inflammation as COPD progresses.
We agree with Dr. Bhowmik that the sentence in the Discussionwas incorrectly written. We should have stated that there wasa negative correlation between HDAC activity and disease severity.
Peter J. Barnes, D.M., D.Sc. Ian M. Adcock, Ph.D. KazuhiroIto, Ph.D. Imperial College London SW3 6LY, United Kingdom p.j.barnes{at}imperial.ac.uk
References
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737-749. [CrossRef][Web of Science][Medline]
Ito K, Adcock IM, Barnes PJ. Knock out of histone deacetylase-2 by RNA interference enhances inflammatory gene expression and reduces glucocorticoid sensitivity in human epithelial cells. Am J Respir Crit Care Med 2004;169:A847-A847. abstract.
Verrotti A, Basciani F, Trotta D, Greco R, Morgese G, Chiarelli F. Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte chemoattractant protein-1. Clin Exp Med 2001;1:133-136. [Medline]
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