Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study

Document Type : Review Article

Authors

1 Systems Biology Institute, Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran

2 Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Sichuan Medical University, Luzhou, Sichuan, China

Abstract

Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD) and compared with mustard lung.

Keywords


1.   Case RA, Lea AJ. Mustard gas poisoning, chronic bronchitis, and lung cancer; an investigation into the possibility that poisoning by mustard gas in the 1914-18 war might be a factor in the production of neoplasia. Br J Prev Soc Med 1955; 9:62-72.
2.   Niu T, Matijasevic Z, Austin-Ritchie P, Stering A, Ludlum DB. A 32P-postlabeling method for the detection of adducts in the DNA of human fibroblasts exposed to sulfur mustard. Chem Biol Interact 1996; 100:77-84.
3.   Ludlum DB, Kent S, Mehta JR. Formation of O6-ethylthioethylguanine in DNA by reaction with the sulfur mustard, chloroethyl sulfide, and its apparent lack of repair by O6-alkylguanine-DNA alkyltransferase. Carcinogenesis 1986; 7:1203-1206.
4.   Jowsey PA, Williams FM, Blain PG. DNA damage responses in cells exposed to sulphur mustard. Toxicol Lett 2012; 209:1-10.
5.   Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281:1309-1312.
6.   Nguewa PA, Fuertes MA, Alonso C, Perez JM. Pharmacological modulation of Poly(ADP-ribose) polymerase-mediated cell death: exploitation in cancer chemotherapy. Mol Pharmacol 2003; 64: 1007-1014.
7.   Chiarugi A, Moskowitz MA. Cell biology. PARP-1--a perpetrator of apoptotic cell death? Science 2002; 297:200-201.
8.   Kehe K, Raithel K, Kreppel H, Jochum M, Worek F, Thiermann H. Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells. Arch Toxicol 2008; 82:461-470.
9.   GP. W. Studies related to the mechanisms of cytotoxic alkylating agents: a review. Cancer Res 1962; 22:651-688.
10. Ghanei M. Respiratory Diseases. Rijeka, Croatia: InTech; 2012.
11. Majid Shohrati IK, Amin Saburi, Hossein Khalili, Mostafa Ghanei. The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review. Inhalation Toxicology 2014; 26: 507-523.
12. Boskabady MH, Farhadi J. The possible prophylactic effect of Nigella sativa seed aqueous extract on respiratory symptoms and pulmonary function tests on chemical war victims: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med 2008; 14:1137-1144.
13. Hamid Saber AS, Mostafa Ghanei. Clinical and paraclinical guidelines for management of sulfur mustard induced bronchiolitis obliterans; from bench to bedside. Inhalation Toxicology 2012; 24:900-906.
14. Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respir Res 2006; 7:21.
15. Pohanka M, Sobotka J, Jilkova M, Stetina R. Oxidative stress after sulfur mustard intoxication and its reduction by melatonin: efficacy of antioxidant therapy during serious intoxication. Drug Chem Toxicol 2011; 34:85-91.
16. Naghii MR. Sulfur mustard intoxication, oxidative stress, and antioxidants. Mil Med 2002; 167:573-575.
17. Pant SC, Vijayaraghavan R, Kannan GM, Ganesan K. Sulphur mustard induced oxidative stress and its prevention by sodium 2,3-dimercapto propane sulphonic acid (DMPS) in mice. Biomed Environ Sci 2000; 13:225-232.
18. Ghanei M, Harandi AA. Molecular and cellular mechanism of lung injuries due to exposure to sulfur mustard: a review. Inhal Toxicol 2011; 23:363-371.
19. Repine JE BA, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997:341-357.
20. Boskabady MH, Amery S, Vahedi N, Khakzad MR. The effect of vitamin E on tracheal responsiveness and lung inflammation in sulfur mustard exposed guinea pigs. Inhal Toxicol 2011; 23:157-165.
21. Rahman I. Oxidative stress in pathogenesis of chronic obstructive pulmonary disease: cellular and molecular mechanisms. Cell Biochem Biophys 2005; 43:167-188.
22. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol 2003; 36:95-109.
23. Carter AB, Monick MM, Hunninghake GW. Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Respir Cell Mol Biol 1999; 20: 751-758.
24. Barreiro E, Fermoselle C, Mateu-Jimenez M, Sanchez-Font A, Pijuan L, Gea J, et al. Oxidative stress and inflammation in the normal airways and blood of patients with lung cancer and COPD. Free Radic Biol Med 2013; 65:859-71.
25. Radi R, Cassina A, Hodara R. Nitric oxide and peroxynitrite interactions with mitochondria. Biol Chem 2002; 383:401-409.
26. Reiter TA. NO* chemistry: a diversity of targets in the cell. Redox Rep 2006;  11:194-206.
27. Szabo C. Poly(ADP-ribose) polymerase activation by reactive nitrogen species--relevance for the pathogenesis of inflammation. Nitric Oxide 2006; 14: 169-179.
28. Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Yorek MA, et al. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001; 50:1927-1937.
29. Paromov V, Qui M, Yang H, Smith M, Stone WL. The influence of N-acetyl-L-cysteine on oxidative stress and nitric oxide synthesis in stimulated macrophages treated with a mustard gas analogue. BMC Cell Biol 2008; 9:33.
30. Gould NS, White CW, Day BJ. A role for mitochondrial oxidative stress in sulfur mustard analog 2-chloroethyl ethyl sulfide-induced lung cell injury and antioxidant protection. J Pharmacol Exp Ther 2009; 328: 732-739.
31. Vijayaraghavan R, Sugendran K, Pant SC, Husain K, Malhotra RC. Dermal intoxication of mice with bis(2-chloroethyl)sulphide and the protective effect of flavonoids. Toxicology 1991; 69:35-42.
32. Mehrani H, Ghanei M, Aslani J, Tabatabaei Z. Plasma proteomic profile of sulfur mustard exposed lung diseases patients using 2-dimensional gel electrophoresis. Clin Proteomics 2011; 8: 2.
33. Shahriary A, Mehrani H, Ghanei M, Parvin S. Comparative proteome analysis of peripheral neutrophils from sulfur mustard-exposed and COPD patients. J Immunotoxicol 2015; 12:132-139.
34. Ghazanfari T, Faghihzadeh S, Aragizadeh H, Soroush MR, Yaraee R, Mohammad Hassan Z, Foroutan A, Vaez-Mahdavi MR, Javadi MA, Moaiedmohseni S, et al. Sardasht-Iran cohort study of chemical warfare victims: design and methods. Arch Iran Med 2009; 12:5-14.
35. Ghazanfari T, Kariminia A, Yaraee R, Faghihzadeh S, Ardestani SK, Ebtekar M, et al. Long term impact of sulfur mustard exposure on peripheral blood mononuclear subpopulations - Sardasht-Iran Cohort Study (SICS). Int Immunopharmacol 2013; 17:931-935.
36. Mostafa Ghanei AAH. Molecular and cellular mechanism of lung injuries due to exposure to sulfur mustard: a review. Inhal Toxicol 2011; 23:363-371.
37. Boskabady MH, Vahedi N, Amery S, Khakzad MR. The effect of Nigella sativa alone, and in combination with dexamethasone, on tracheal muscle responsiveness and lung inflammation in sulfur mustard exposed guinea pigs. J Ethnopharmacol 2011; 137:1028-1034.
38. Boskabady MH, Attaran D, Shaffei MN. Airway responses to salbutamol after exposure to chemical warfare. Respirology. 2008; 13: 288-293.
39. Boskabady MH, Tabatabayee A, Amiri S, Vahedi N. The effect of vitamin E on pathological changes in kidney and liver of sulphur mustard-exposed guinea pigs. Toxicol Ind Health 2012; 28: 216-221.
40. Brigati C, Banelli B, di Vinci A, Casciano I, Allemanni G, Forlani A, et al. Inflammation, HIF-1, and the epigenetics that follows. Mediators  Inflamm 2010; 2010:263914.
41. Mechali M. DNA replication origins: from sequence specificity to epigenetics. Nat Rev Genet 2001; 2:640-5.
42. Cheung P LP. Epigenetic regulation by histone methylation and histone variants. Mol Endocrinol 2005; 19:563-573.
43. Lee KK WJ. Histone acetyltransferase complexes: one size doesn’t fit all. Nat Rev Mol Cell Biol 2007; 8: 284-295.
44. Wright RJ. Epidemiology of stress and asthma: from constricting communities and fragile families to epigenetics. Immunol Allergy Clin North Am 2011; 31:19-39.
45. Durham A, Chou PC, Kirkham P, Adcock IM. Epigenetics in asthma and other inflammatory lung diseases. Epigenomics 2010; 2: 523-537.
46. Li CY, Guo XJ, Gan LX. [The epigenetics in asthma]. Zhonghua Jie He He Hu Xi Za Zhi 2009; 32:759-761.
47. Lovinsky-Desir S, Miller RL. Epigenetics, asthma, and allergic diseases: a review of the latest advancements. Curr Allergy Asthma Rep 2012; 12: 211-220.
48. Langevin SM, Kratzke RA, Kelsey KT. Epigenetics of lung cancer. Transl Res 2014; 165:74-90.
49. Sundar IK, Mullapudi N, Yao H, Spivack SD, Rahman I. Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics. Curr Opin Pulm Med 2011; 17: 279-285.
50. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol. 2010; 126: 453-65.
51. Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest 2011; 139: 640-647.
52. Shaheen SO, Adcock IM. The developmental origins of asthma: does epigenetics hold the key? Am J Respir Crit Care Med 2009; 180: 690-691.
53. Stower H. Epigenetics: Dynamic DNA methylation. Nat Rev Genet 2011; 13:75.
54. Lan F, Shi Y. Epigenetic regulation: methylation of histone and non-histone proteins. Sci China C Life Sci 2009; 52: 311-322.
55. Durham AL, Wiegman C, Adcock IM. Epigenetics of asthma. Biochim Biophys Acta 2011; 1810: 1103-1109.
56. Kabesch M, Adcock IM. Epigenetics in asthma and COPD. Biochimie 2012; 94: 2231-2241.
57. Koppelman GH, Nawijn MC. Recent advances in the epigenetics and genomics of asthma. Curr Opin Allergy Clin Immunol 2011; 11: 414-419.
58. Lee SH, Park JS, Park CS. The search for genetic variants and epigenetics related to asthma. Allergy Asthma Immunol Res 2011; 3: 236-244.
59. Bartova E, Krejci J, Hajek R, Harnicarova A, Kozubek S. Chromatin structure and epigenetics of tumour cells: a review. Cardiovasc Hematol Disord Drug Targets 2009; 9: 51-61.
60. Diaw L, Woodson K, Gillespie JW. Prostate cancer epigenetics: a review on gene regulation. Gene Regul Syst Bio 2007; 1: 313-325.
61. Katoh M. Therapeutics targeting angiogenesis: Genetics and epigenetics, extracellular miRNAs and signaling networks (Review). Int J Mol Med 2013; 32:763-767.
62. Mungall AJ. Meeting review: Epigenetics in Development and Disease. Comp Funct Genomics 2002; 3: 277-281.
63. Weber M, Schubeler D. Genomic patterns of DNA methylation: targets and function of an epigenetic mark. Curr Opin Cell Biol 2007; 19: 273-280.
64. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349: 2042-2054.
65. Illingworth RSB, A. P. CpG islands--'a rough guide'. FEBS Lett 2009; 583: 1713-1720.
66. Maric NP, Svrakic DM. Why schizophrenia genetics needs epigenetics: a review. Psychiatr Danub 2012; 24: 2-18.
67. Cheng X, Blumenthal RM. Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. Biochemistry 2010; 49:2999-3008.
68. McCabe MT, Brandes JC, Vertino PM. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 2009; 15: 3927-3937.
69. Bhattacharya SK, Ramchandani S, Cervoni N, Szyf M. A mammalian protein with specific demethylase activity for mCpG DNA. Nature 1999; 397:579-583.
70. Anest V HJ, Cogswell PC, Steinbrecher KA, Strahl BD, Baldwin AS A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature 2003; 423:659-663.
71. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011; 333:1300-1303.
72. Benakanakere MR LQ, Eskan MA, Singh AV, Zhao J, Galicia JC, et al. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J Biol Chem 2009; 284: 23107-23115.
73. Zhang H, Zhu JK. Active DNA demethylation in plants and animals. Cold Spring Harb Symp Quant Biol 2012; 77:161-173.
74. Zhu JK. Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet. 2009; 43: 143-66.
75. Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 2013; 339: 448-452.
76. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 2009; 323: 1074-1077.
77. Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 2011; 145: 423-434.
78. Campos EI, Reinberg D. Histones: annotating chromatin. Annu Rev Genet 2009; 43: 559-599.
79. Rajendrasozhan S, Yang SR, Edirisinghe I, Yao H, Adenuga D, Rahman I. Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD. Antioxid Redox Signal 2008; 10: 799-811.
80. Wierda RJ, Geutskens SB, Jukema JW, Quax PH, van den Elsen PJ. Epigenetics in atherosclerosis and inflammation. J Cell Mol Med 2010; 14: 1225-1240.
81. Shanmugam MK, Sethi G. Role of epigenetics in inflammation-associated diseases. Subcell Biochem 2012; 61: 627-657.
82. Cruickshank MN, Besant P, Ulgiati D. The impact of histone post-translational modifications on developmental gene regulation. Amino Acids 2010; 39: 1087-1105.
83. Yla-Herttuala S, Glass CK. Review focus on epigenetics and the histone code in vascular biology. Cardiovasc Res 2011; 90: 402-403.
84. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Histone acetylation and disease. Cell Mol Life Sci. 2001; 58: 728-736.
85. Adamopoulou E, Naumann U. HDAC inhibitors and their potential applications to glioblastoma therapy. Oncoimmunology 2013; 2: e25219.
86. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest 2006; 129: 151-155.
87. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129: 823-837.
88. Cheung P, Lau P. Epigenetic regulation by histone methylation and histone variants. Mol Endocrinol 2005; 19: 563-573.
89. Bhan A, Mandal SS. Long Noncoding RNAs: Emerging Stars in Gene Regulation, Epigenetics and Human Disease. Chem Med Chem 2014; 9:1932-1956.
90. Blelloch R, Gutkind JS. Epigenetics, noncoding RNAs, and cell signaling--crossroads in the regulation of cell fate decisions. Curr Opin Cell Biol 2013; 25: 149-151.
91. Friedman JM, Jones PA, Liang G. The tumor suppressor microRNA-101 becomes an epigenetic player by targeting the polycomb group protein EZH2 in cancer. Cell Cycle 2009; 8: 2313-2314.
92. Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 2009; 31: 965-973.
93. Tili E, Michaille JJ. Resveratrol, MicroRNAs, Inflammation, and Cancer. J Nucleic Acids 2011; 2011: 102431.
94. Sonkoly E, Pivarcsi A. microRNAs in inflammation. Int Rev Immunol 2009; 28: 535-561.
95. Cao J. The functional role of long non-coding RNAs and epigenetics. Biol Proced Online 2014; 16: 11.
96. Beckedorff FC, Amaral MS, Deocesano-Pereira C, Verjovski-Almeida S. Long non-coding RNAs and their implications in cancer epigenetics. Biosci Rep 2013; 33.
97. Najafi A, Masoudi-Nejad A, Imani Fooladi AA, Ghanei M, Nourani MR. Microarray gene expression analysis of the human airway in patients exposed to sulfur mustard. J Recept Signal Transduct Res 2014; 34: 283-289.
98. Medzhitov R, Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol 2009; 9: 692-703.
99. Piantadosi CA, Suliman HB. Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes. Biochim Biophys Acta 2012; 1820: 532-541.
100.  Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454: 428-35.
101.  McKeever T LS, Smith C, Hubbard R. The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database. Am J Respir Crit Care Med 2002; 166: 827-832.
102.  Chowdhury S, Ammanamanchi S, Howell GM. Epigenetic Targeting of Transforming Growth Factor beta Receptor II and Implications for Cancer Therapy. Mol Cell Pharmacol 2009; 1: 57-70.
103.  Allfrey VG, Faulkner R, Mirsky AE. Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis. Proc Natl Acad Sci USA 1964; 51:786-794.
104.  Kipnis E, Dessein R. Bacterial modulation of Tregs/Th17 in intestinal disease: a balancing act? Inflamm Bowel Dis 2012; 18: 1389-1390.
105.  Ballestar E. Epigenetics lessons from twins: prospects for autoimmune disease. Clin Rev Allergy Immunol 2010; 39: 30-41.
106.  Krupanidhi S, Sedimbi SK, Sanjeevi CB. Epigenetics and epigenetic mechanisms in disease with emphasis on autoimmune diseases. J Assoc Physicians India 2008; 56: 875-880.
107.  Callinan PA FA. The emerging science of epigenomics. Hum Mol Genet 2006; 15: 95–101.
108.  Marwick JA, Ito K, Adcock IM, Kirkham PA. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets 2007; 11: 745-55.
109.  Korkmaz A, Yaren H, Kunak Zl, Uysal B, Kurt B, Topal T, et al. Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results. Interdisc Toxicol 2008; 1: 236–241.
110.  Mielcarek M, Benn CL, Franklin SA, Smith DL, Woodman B, Marks PA, Bates GP. SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease. PLoS One 2011; 6: e27746.
111.  Mosley AL, Ozcan S. The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J Biol Chem 2004; 279: 54241-54247.
112.  Wagner M, Brosch G, Zwerschke W, Seto E, Loidl P, Jansen-Durr P. Histone deacetylases in replicative senescence: evidence for a senescence-specific form of HDAC-2. FEBS Lett. 2001; 499: 101-6.
113.  Ito K, Hanazawa T, Tomita K, Barnes PJ, Adcock IM. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun 2004; 315: 240-245.
114.  Egger G LG, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457-463.
115.  Ghanei M, Harandi AA. Long term consequences from exposure to sulfur mustard: a review. Inhal Toxicol 2007; 19: 451-456.
116.  Pourfarzam S, Ghazanfari T, Yaraee R, Ghasemi H, Hassan ZM, Faghihzadeh S, Ardestani SK, Kariminia A, Fallahi F, Soroush MR, et al. Serum levels of IL-8 and IL-6 in the long term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study. Int Immunopharmacol 2009; 9: 1482-1488.
117.  Panahi Y, Ghanei M, Ghabili K, Ansarin K, Aslanabadi S, Poursaleh Z, Eslam Jamal Golzari S, Etemadi J, Khalili M, Mohajel Shoja M. Acute and chronic pathological effects of sulfur mustard on genitourinary system and male fertility. Urol J 2013; 10: 837-846.
118.  Ghanei M, Vosoghi AA. An epidemiologic study to screen for chronic myelocytic leukemia in war victims exposed to mustard gas. Environ Health Perspect 2002; 110: 519-521.
119.  Emad A, Emad Y. Increased granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) levels in BAL fluid from patients with sulfur mustard gas-induced pulmonary fibrosis. J Aerosol Med 2007; 20: 352-360.
120.  Mostafa Ghanei HF, Mohammad Mir Mohammad, Jafar Aslani, Fariborz Nematizadeh. Long-Term Respiratory Disorders of Claimers with Subclinical Exposure to Chemical Warfare Agents. Inhalation Toxicology 2004; 16: 491-495.
121.  Gerecke DR, Chen M, Isukapalli SS, Gordon MK, Chang YC, Tong W, Androulakis IP, Georgopoulos PG. Differential gene expression profiling of mouse skin after sulfur mustard exposure: Extended time response and inhibitor effect. Toxicol Appl Pharmacol 2009; 234: 156-165.
122.  Nishimoto Y, Yamakido M, Ishioka S, Shigenobu T, Yukutake M. Epidemiological studies of lung cancer in Japanese mustard gas workers. Princess Takamatsu Symp 1987; 18: 95-101.
123.  Norman JE, Jr. Lung cancer mortality in World War I veterans with mustard-gas injury: 1919-1965. J Natl Cancer Inst 1975; 54: 311-317.
124.  Emad A, Rezaian GR. Characteristics of bronchoalveolar lavage fluid in patients with sulfur mustard gas-induced asthma or chronic bronchitis. Am J Med 1999; 106: 625-628.
125.  Tang FR, Loke WK. Sulfur mustard and respiratory diseases. Crit Rev Toxicol. 2012; 42: 688-702.
126.  Paromov V, Suntres Z, Smith M, Stone WL. Sulfur mustard toxicity following dermal exposure: role of oxidative stress, and antioxidant therapy. J Burns Wounds. 2007; 7: e7.
127.  Emad A, Emad V. Elevated levels of MCP-1, MIP-alpha and MIP-1 beta in the bronchoalveolar lavage (BAL) fluid of patients with mustard gas-induced pulmonary fibrosis. Toxicology 2007; 240: 60-69.
128.  Emad A, Emad Y. Relationship between eosinophilia and levels of chemokines (CCL5 and CCL11) and IL-5 in bronchoalveolar lavage fluid of patients with mustard gas-induced pulmonary fibrosis. J Clin Immunol 2007; 27: 605-612.
129.  Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, Hagood JS. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol 2008; 39: 610-618.
130.  Korkmaz A, Tan DX, Reiter RJ. Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies. Interdiscip Toxicol. 2008; 1: 22-6.
131.  Shuto T, Furuta T, Oba M, Xu H, Li JD, Cheung J, Gruenert DC, Uehara A, Suico MA, Okiyoneda T, et al. Promoter hypomethylation of Toll-like receptor-2 gene is associated with increased proinflammatory response toward bacterial peptidoglycan in cystic fibrosis bronchial epithelial cells. FASEB J. 2006; 20: 782-784.
132.  Takahashi K SY, Hosono A, Kaminogawa S. Epigenetic regula-tion of TLR4 gene expression in intestinal epithelial cells for the main-tenance of intestinal homeostasis. J Immunol 2009; 183: 6522-6529.
133.  Sullivan KE RA, Dietzmann K, Suriano AR, Kocieda VP, Stewart M, et al. Epigenetic regulation of tumor necrosis factor alpha. Mol Cell Biol 2007; 27: 5147-5160.
134.  Katayama Y TM, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun 2009; 388: 496-500.
135.  Hu JL ZB, Zhang RR, Zhang KL, Zhou JQ, Xu GL. The N-terminus of histone H3 is required for de novo DNA methylation in chromatin. Proc Natl Acad Sci USA 2009; 106: 22187-22192.
136.  Ishii M WH, Corsa CA, Liu T, Coelho AL, Allen RM, et al. Epigenetic regulation of the alternatively activated macrophage pheno-type. Blood 2009; 114: 3244-3254.
137.  De Santa F NV, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S, Testa G, Sung WK, Wei CL, Natoli G. Jmjd3 contributes to the control of gene expression in LPS-activated macrophage. EMBO J 2009; 28: 3341-3352.
138.  El Gazzar M YB, Chen X, Hu J, Hawkins GA, McCall CE G9a and HP1 couple histone and DNA methylation to TNFαtranscription silencing during endotoxin tolerance. J Biol Chem 2008; 283: 32198-32208.
139.  Visel A BM, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Ren B, Rubin EM, Pennacchio LA. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature. 2009: 854-858.
140.  Yang J PY, Zhang H, Xu X, Laine GA, Dellsperger KC, Zhang C. Feed-forward signaling of TNF-alpha and NF-kappaB via IKK-beta pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice. F Am J Physiol Heart Circ Physiol. 2009; 296: 1850-1858.
141.  Taganov KD BM, Chang KJ, Baltimore D NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 2006; 103: 12481-12486.
142.  O’Connell RM CA, Rao DS, Baltimore D. Inositol phos-phatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA 2009; 106: 7113-7118.
143.  Liu G FA, Yang Y, Park YJ, Tsuruta Y, Abraham E. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regu-lates murine macrophage inflammatory responses. Proc Natl Acad Sci USA 2009; 160: 15819-15824.
144.  Fabbri M GR, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3. Proc Natl Acad Sci USA. 2007; 104: 15805-15810.
145.  Hu JL ZB, Zhang RR, Zhang KL, Zhou JQ, Xu GL. The N-terminus of histone H3 is required for de novo DNA methylation in chromatin. Proc Natl Acad Sci USA. 2009; 106: 22187-22192.
146.  Tuddenham L WG, Ntounia-Fousara S, Waters J, Hajihosseini MK, Clark I, et al. The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells. FEBS Lett. 2006; 580: 4214-4217.
147.  Esposito E, Iacono A, Muia C, Crisafulli C, Mattace Raso G, Bramanti P, Meli R, Cuzzocrea S. Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res. 2008; 44: 78-87.
148.  Deng WG, Tang ST, Tseng HP, Wu KK. Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood. 2006; 108: 518-524.
149.  Nourani MR, Ebrahimi M, Roudkenar MH, Vahedi E, Ghanei M, Imani Fooladi AA. Sulfur mustard induces expression of metallothionein-1A in human airway epithelial cells. Int J Gen Med. 2011; 4: 413-419.
150.  Mirbagheri L, Habibi Roudkenar M, Imani Fooladi AA, Ghanei M, Nourani MR. Downregulation of super oxide dismutase level in protein might be due to sulfur mustard induced toxicity in lung. Iran J Allergy Asthma Immunol. 2013; 12: 153-160.
151.  Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011; 208: 1339-50.
152.  Yunes Panahi RM-L, Farshid Alaeddini, Mohammad Mehdi Naghizadeh, Jafar Aslani, Mostafa Ghanei. Furosemide Inhalation in Dyspnea of Mustard Gas-Exposed Patients: A Triple-Blind Randomized Study. Inhalation Toxicology. 2008; 20: 873-877.
153.  Adelipour M, Imani Fooladi AA, Yazdani S, Vahedi E, Ghanei M, Nourani MR. Smad molecules expression pattern in human bronchial airway induced by sulfur mustard. Iran J Allergy Asthma Immunol. 2011; 10: 147-154.
154.  Mostafa Ghanei AAH. Molecular and cellular mechanism of lung injuries due to exposure to sulfur mustard: a review. Inhalation Toxicology. 2011; 23: 363-371.
155.  Mirsadraee M, Attaran D, Boskabady MH, Towhidi M. Airway hyperresponsiveness to methacholine in chemical warfare victims. Respiration. 2005; 72: 523-528.
156.  Ghanei M MN, Ali Morad Kosar, Ali Amini Harandi, Nicholas S. Hopkinson, Zohreh Poursaleh. Long-term pulmonary complications of chemical warfare agent exposure in Iraqi Kurdish civilians. Inhalation Toxicology. 2010; 22: 719-724.
157.  Panahi Y, Ghanei M, Vahedi E, Ghazvini A, Parvin S, Madanchi N, Bagheri M, Sahebkar A. Effect of recombinant human IFNgamma in the treatment of chronic pulmonary complications due to sulfur mustard intoxication. J Immunotoxicol. 2014; 11: 72-77.
158.  Panahi Y, Sarayani A, Beiraghdar F, Amiri M, Davoudi SM, Sahebkar A. Management of sulfur mustard-induced chronic pruritus: a review of clinical trials. Cutan Ocul Toxicol. 2012; 31: 220-225.