24 Sulfur mustard and use of melatonin A. Korkmaz, D-X. Tan & R.J. Reiter epigenetic errors could be a major contributor to human dis- eases (Jiang et al., 2004). Epigenotype is generally accepted as being less stable than the genetic system, and more sensi- tive to chemical toxicants (Bombail et al., 2004; McLachlan et al., 2001). SM may perturb the epigenetic environment of transcription factors such as NF-κB and AP-1 and/or pro- inflammatory genes such as TNF-α and ILs. Lessons-learned from Treatment of Patients with Chronic Obstructive Pulmonary Diseases One of the major problems in the treatment of chronic obstructive pulmonary diseases (COPD) is glucocorticoid resistance. Although inhaled glucocorticoids are highly effective in asthma, they provide relatively little therapeutic benefit in COPD, despite the fact that active airway and lung inflammation is present. This may reflect that the inflam- mation in COPD is not suppressed by glucocorticoids, with no reduction in inflammatory cells, cytokines or proteases in induced sputum even with high doses of inhaled and oral glucocorticoids (Loppow et  al., 2001). Furthermore, histological analysis of peripheral airways of patients with severe COPD shows an intense inflammatory response, despite treatment with high doses of inhaled glucocorticoids (Hogg et al., 2004). There is increasing evidence for an active steroid resistance mechanism in COPD, as glucocorticoids fail to inhibit cytokines (e.g., ILs and TNF-α) that they normally suppress. The predominant effect of glucocorticoids is to switch off multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules and inf lammatory enzymes) that have been activated during the chronic inflammatory process. The increased expression of most of these inflammatory proteins is regulated at the level of gene transcription through the activation of pro-inflammatory transcription factors, such as nuclear NF-κB and AP-1. The molecular pathways involved in regulating inflammatory gene expression are now being delineated and it is now clear that chromatin remodeling and a variety of epigenetic mechanisms play a critical role in the transcriptional control of genes. Stimuli that switch on inflammatory genes do so by changing the chromatin structure of the inflammatory gene, whereas glucocorticoids reverse this process. Glucocorticoids produce their effect on responsive cells by activating the glucocorticoid receptor (GR) to directly or indirectly regulate the transcription of target genes. Most of the anti-inflammatory actions of glucocorticoids are due to suppression of the actions of AP-1 and NF-κB (Barnes, 2006). The activated GR may directly bind to nuclear receptor co-activators (e.g., p300/CBP) to inhibit their HAT activity, thus preventing the subsequent histone acetylation and chromatin remodeling and leads to inhibition of AP-1 and NF-κB-induced pro-inflammatory gene expression such as TNF-α, IL-1β and adhesion molecules (Adcock et  al., 2004). Another mechanism is to reverse this process by deacetylating the hyper-acetylated histones through the recruitment of HDAC-2 to the activated co-activator com- plex (Ito et al., 2006). This process results in rewinding and iSSn: 1337-6853 (print version) | 1337-9569 (electronic version) compaction of DNA, exclusion of RNA polymerase, and sup- pression of inflammatory gene transcription. This mecha- nism could account for the anti-inflammatory effect of glu- cocorticoids in inflammatory diseases (Adcock et al., 2004). Patients with COPD has been shown to have a progres- sive reduction in total HDAC activity that reflects the sever- ity of the disease (Ito et al., 2005; Ito et al., 2006). There is also a reduction in total HDAC activity in peripheral lung, bronchial biopsy specimens, and alveolar macrophages from COPD patients, and this is correlated with disease severity and with increased gene expression of IL-8 (Ito et al., 2005). HDAC activity is reduced in alveolar macrophages of cigarette smokers compared to nonsmokers, and this is cor- related with increased expression of inflammatory genes in these cells (Ito et al., 2001). Importantly, HDAC-2 has been found to mediate the deacetylation of the GR that enables NF-κB suppression (Ito et al., 2006). It was suggested that HDAC-2 is a key enzyme involved in the suppression of NF-κB-mediated inflammatory gene expression. Therefore, HDAC-2 reduction is involved both glucocorticoid-resistance and NF-κB-mediated inflammatory gene expression. The importance of this mechanism in glucocorticoid-insensitive COPD disease is emphasized by over-expression of HDAC-2, which restores glucocorticoid sensitivity in primary cells from these patients. The reasons for the reduction in HDAC, particularly HDAC-2, in COPD are not yet com- pletely understood. However, there is increasing evidence that this may be due to inactivation of the enzyme of nitro- oxidative stress, in particular ONOO– (Marwick et al., 2004; Moodie et al., 2004; Rahman et al., 2004). Interestingly, it was reported that the bronchoalveolar lavage cellular constituents of patients with SM-induced asthma and chronic bronchitis (most frequent delayed lung toxicities) are similar to those that have been observed previously in patients with asthma and chronic bronchitis from other common causes (Emad and Rezaian, 1999). They also revealed a number of pathophysiological simi- larities between SM-induced lung toxicity and pulmonary fibrosis (Emad and Emad, 2007) as well as bronchiectasis. Therefore, it is speculated that SM-induced delayed toxicity may be mediated by epigenetic perturbations at least in lung tissue. Further experimental studies are needed to clarify the pathophysiological mechanism. Possible Beneficial Effects of Melatonin Against Delayed SM Toxicity Melatonin shows beneficial effects against SM-induced acute toxicity as a multifunctional antioxidant and ONOO– scavenging agent in both in vivo and in vitro (Sourdeval et al., 2006; Ucar et al., 2007). Also, several well-explained effects of melatonin seem to derive from epigenetic actions of the indolamine. For example, melatonin possesses genomic actions and regulates the expression of several genes. Melatonin influences cellular mRNA levels for antioxidant enzymes under both physiological conditions and during elevated oxidative stress (Rodriguez et al., 2004). Consistent evidence suggests that melatonin modulates antioxidant