Document Type : Original Research


1 Dept. of Biology, Faculty of Basic Sciences, Shahid Bahonar University of Kerman, Kerman, Iran

2 Immunoregulation Research Center, Shahed University, Tehran, Iran

3 Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran

4 Dept. of Immunology, Tarbiat Moddares University, Tehran, Iran


Background & objective: Pruritus is the most frequent chronic dermal complication of sulfur mustard (SM), which negatively influences the quality of life. Exact pathophysiology of SM-induced itching is unknown. The current study aimed at evaluating the possible association between SM-induced itching and the serum levels of matrix metalloproteinase (MMP)-9 and their endogenous inhibitors, and serum levels of soluble forms of selectins (sL-, sP-, and sE-selectins) as adhesion molecules involved in the development of different inflammatory reactions.
Methods: Serum levels of MMP-9, MMP-9/ tissue inhibitors of metalloproteinases (TIMPs), and selectins were measured by the enzyme-linked immunosorbent assay (ELISA), and compared between the groups (n=368) with and without itching, and matched control groups (n=126).
Results: Serum levels of MMP-9 were significantly higher in the SM exposed group with itching, compared with that of the group without itching (medians: 894 and 624 pg/mL respectively; P-value =0.034). There was no relationship between the serum levels of MMP-9/TIMP-1, MMP-9/TIMP-2, MMP-9/TIMP-4, and itching in the patients exposed to SM. Median serum levels of sE- and sL-selectins in the exposed group with itching were higher than those of the exposed group without itching. These differences were statistically insignificant (P-values =0.084 and 0.095, respectively).
Conclusion: According to the results of the current study, the increased serum levels of MMP-9 and selectins 20 years after exposure may play role in the pathogenesis and persistence of SM-induced itching in the exposed individuals.


Main Subjects

1. Moin A, Ghazanfari T, Davoudi SM, Emadi N, Panahi Y, Hassan ZM, et al. Long-term skin findings of sulfur mustard exposure on the civilians of Sardasht, Iran. Toxin Reviews. 2009;28(1):24-9.
2. Fekri A. Late cutaneous complications in chemical warfare victims in Kerman province. Journal of Kerman University of Medical Sciences. 1995;2(3):108-19.
3. Toosi P, Amir jA, Heydarian M, Keshvarz S, Fayaz M. Delayed Cutaneous complications in soldiers attacked by chemical agents. Pejouhandeh. 2002;7:209–12.
4. Hefazi M, Maleki M, Mahmoudi M, Tabatabaee A, Balali‐Mood M. Delayed complications of sulfur mustard poisoning in the skin and the immune system of Iranian veterans 16–20 years after exposure. International journal of dermatology. 2006;45(9):1025-31.
5. Heidari M, Karaminejad Ranjbar M, Ansari H. Prevalence of late toxic complication in chemical warfare victims. Daneshvar Medicine, Scientific Research Journal of Shahed University. 1999;7:67-72.
6. Greaves M. Pruritus. In: Bolognia JL, Jorizzo J, Rapini R, eds. Dermatology Edinburgh: Mosby. 2003:pp. 85-90.
7. William J, Berger T, Elston D. Andrews' diseases of the skin. 10 ed.: Philadelphia: WB Saunders; 2006.
8. Norton S. The skin in bioterrorism and biologic warfare. In: Wolff K, Goldsmith LA, Katz SI, Glchrest BA, Paller AS, Leffell DJ, eds. 7th ed.: New York: McGraw Hill; 2008.
9. Lateef F. Of pruritus and terrorism. Singapore Med J. 2007;48(5):380-2.
10. Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy. 2012;42(1):8-19.
11. Heyl T. Brachioradial pruritus. Archives of dermatology. 1983;119(2):115-6.
12. Moin A, Khamesipour A, Hassan ZM, Ebtekar M, Davoudi SM, Vaez-Mahdavi MR, et al. Pro-inflammatory cytokines among individuals with skin findings long-term after sulfur mustard exposure: Sardasht-Iran Cohort Study. Int Immunopharmacol. 2013;17(3):986-90.
13. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiological reviews. 2006;86(4):1309-79.
14. Dziankowska-Bartkowiak B, Waszczykowska E, Żebrowska A. The role of metaloproteinases and their inhibitors in the patomechanism of skin diseases. Alerg Astma Immun. 2004;9:71-9.
15. Groneberg D, Bester C, Grützkau A, Serowka F, Fischer A, Henz B, et al. Mast cells and vasculature in atopic dermatitis–potential stimulus of neoangiogenesis. Allergy. 2005;60(1):90-7.
16. Fakhoury H, Hillarby M, Weiss J. Increased gelatinase activity in systemic sclerosis dermal fibroblast cultures with unaltered gelatinase A mRNA expression. Journal of dermatological science. 2002;29(1):62-9.
17. Suomela S, Kariniemi AL, Snellman E, Saarialho‐Kere U. Metalloelastase (MMP‐12) and 92‐kDa gelatinase (MMP‐9) as well as their inhibitors, TIMP‐1 and‐3, are expressed in psoriatic lesions. Experimental dermatology. 2001;10(3):175-83.
18. Suomela S, Kariniemi A-L, Impola U, Karvonen S-L, Snellman E, Uurasmaa T, et al. Matrix metalloproteinase-19 is expressed by keratinocytes in psoriasis. Acta dermato-venereologica. 2003;83(2):108-14.
19. Sekhon BS. Matrix metalloproteinases-an overview. Res Rep Biol. 2010;1:1-20.
20. Bell J, McQueen D, Rees J. Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in BalbC mice. British journal of pharmacology. 2004;142(2):374-80.
21. Gutgesell C, Heise S, Seubert A, Stichtenoth D, Frölich J, Neumann C. Comparison of different activity parameters in atopic dermatitis: correlation with clinical scores. British Journal of Dermatology. 2002;147(5):914-9.
22. Schon MP. Inhibitors of selectin functions in the treatment of inflammatory skin disorders. Ther Clin Risk Manag. 2005;1(3):201-8.
23. Ghazanfari T, Faghihzadeh S, Aragizadeh H, Soroush MR, Yaraee R, Mohammad Hassan Z, et al. Sardasht-Iran cohort study of chemical warfare victims: design and methods. Arch Iran Med. 2009;12(1):5-14.
24. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2010;1803(1):55-71.
25. Cawston T. Metalloproteinase inhibitors and the prevention of connective tissue breakdown. Pharmacology & therapeutics. 1996;70(3):163-82.
26. Johnson LL, Dyer R, Hupe DJ. Matrix metalloproteinases. Current opinion in chemical biology. 1998;2(4):466-71.
27. Shohrati M, Haji Hosseini R, Esfandiari MA, Najafian N, Najafian B, Golbedagh A. Serum matrix metalloproteinase levels in patients exposed to sulfur mustard. Iran Red Crescent Med J. 2014;16(3):e15129.
28. Shohrati M, Ahmadi M, Esfandiari MA, Soleimani N, Davari SM, Najafian B. Level of matrix metalloproteinases and their inhibitors in skin tissue samples of sulfur mustard exposed chemical patients. Trauma Monthly. 2011;2011(3, Autumn):163-7.
29. Shakarjian MP, Bhatt P, Gordon MK, Chang YC, Casbohm SL, Rudge TL, et al. Preferential expression of matrix metalloproteinase-9 in mouse skin after sulfur mustard exposure. J Appl Toxicol. 2006;26(3):239-46.
30. Zebrowska A, Wagrowska-Danilewicz M, Danilewicz M, Stasikowska-Kanicka O, Kulczycka-Siennicka L, Wozniacka A, et al. Mediators of mast cells in bullous pemphigoid and dermatitis herpetiformis. Mediators Inflamm. 2014;2014:936545.
31. Tengara S, Tominaga M, Kamo A, Taneda K, Negi O, Ogawa H, et al. Keratinocyte-derived anosmin-1, an extracellular glycoprotein encoded by the X-linked Kallmann syndrome gene, is involved in modulation of epidermal nerve density in atopic dermatitis. Journal of dermatological science. 2010;58(1):64-71.
32. Tominaga M, Takamori K. Recent advances in pathophysiological mechanisms of itch. 2010.
33. Tominaga M, Kamo A, Tengara S, Ogawa H, Takamori K. In vitro model for penetration of sensory nerve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritus. British Journal of Dermatology. 2009;161(5):1028-37.
34. Asaduzzaman M, Rahman M, Jeppsson B, Thorlacius H. P‐selectin glycoprotein‐ligand‐1 regulates pulmonary recruitment of neutrophils in a platelet‐independent manner in abdominal sepsis. British journal of pharmacology. 2009;156(2):307-15.
35. Hayashi S, Abe Ky, Matsuoka H, Goya S, Morishita H, Mori M, et al. Increased level of soluble E-selectin in the serum from patients with idiopathic pulmonary fibrosis. Inflammation. 2004;28(1):1-5.
36. Hall RP, 3rd, Takeuchi F, Benbenisty KM, Streilein RD. Cutaneous endothelial cell activation in normal skin of patients with dermatitis herpetiformis associated with increased serum levels of IL-8, sE-Selectin, and TNF-alpha. J Invest Dermatol. 2006;126(6):1331-7.
37. Thestrup-Pedersen K, Ring J. Atopic Dermatitis. Summary of the 1st Georg Rajka Symposium 1998 and a Literature Review. Acta Dermatovenereologica-Stockholm-. 1999;79:257-64.
38. Barker J, editor. Adhesion molecules in cutaneous inflammation. Ciba Found Symp; 1995.
39. Cordero MM, Casas BB, Reyes RN, Avila CL, del Río NB, Sienra MJ. [Cyclosporin A in atopic dermatitis]. Revista alergia Mexico (Tecamachalco, Puebla, Mexico: 1993). 2001;49(4):129-34.
40. Shimada Y, Sato S, Hasegawa M, Tedder TF, Takehara K. Elevated serum L-selectin levels and abnormal regulation of L-selectin expression on leukocytes in atopic dermatitis: soluble L-selectin levels indicate disease severity. Journal of allergy and clinical immunology. 1999;104(1):163-8.
41. Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch‐associated cutaneous factors. British Journal of Dermatology. 2003;149(4):718-30.
42. Kneuer C, Ehrhardt C, Radomski MW, Bakowsky U. Selectins–potential pharmacological targets? Drug discovery today. 2006;11(21):1034-40.