Original Article
 

Evaluation of Apoptosis in the Lung Tissue of Sulfur Mustard-exposed Individuals

Abstract

Lung exposure to sulfur mustard (SM) results in pulmonary complications, which is the main cause of long-term disability and morbidity. Up to now, the precise mechanisms of SM-induced lung complications has not been identified. The aim of this study was to evaluate apoptosis in the lung tissue of SM-exposed individuals. The study was performed on archived lung paraffin-embedded tissue specimens of21 patients suffering from pulmonary complications due to previous SM exposure and 9 unexposed patients who had undergone lung resections for another lung disease. Evaluation of apoptosis in paraffin-embedded lung tissue sections was performed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and the cleaved caspase-3 immunohistochemistry assays. TUNEL-positive apoptotic features and caspase-3 expression of specimens were significantly higher in the SM-exposed group compared with the control group. This result demonstrates higher apoptosis rate in the SM-exposed group. Furthermore, the majority of positive cells consisted of alveolar epithelial cells in both methods. In conclusion,it seems that exposure to SM may result in increased apoptosis in respiratory epithelium. More studies are needed to evaluate the role of apoptosis in SM-induced lung complications in order to design new and effective therapeutic protocols.

1. Tang FR, Loke WK. Sulfur mustard and respiratory diseases. Crit Rev Toxicol 2012;42(8):688-702.
2. Shariat-Panahi S, Ghazanfari T, Yaraee R, Hassan ZM, Soroush MR, Mahdavi MRV, et al. Long-term rheumatologic complications of sulfur mustard in victims of Sardasht, Iran. Toxin Reviews 2009; 28(1):34-8.
3. Ghanei M, Harandi AA. Long term consequences from exposure to sulfur mustard: a review. Inhal Toxicol 2007;19(5):451-6.
4. Poursaleh Z, Harandi AA, Vahedi E, Ghanei M. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase. Daru 2012;20(1):27.
5. Balali‐Mood M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 2006;99(4):273-82.
6. Sourdeval M, Lemaire C, Deniaud A, Taysse L, Daulon S, Breton P, et al. Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis 2006;11(9):1545-59.
7. Dabrowska MI, Becks LL, Lelli Jr JL, Levee MG, Hinshaw DB. Sulfur mustard induces apoptosis and necrosis in endothelial cells. Toxicology and applied pharmacology.1996;141(2):568-83.
8. Kan RK, Pleva CM, Hamilton TA, Anderson DR, Petrali JP. Sulfur mustard-induced apoptosis in hairless guinea pig skin. Toxicol Pathol 2003;31(2):185-90.

9. Ray R, Keyser B, Benton B, Daher A, Simbulan-Rosenthal CM, Rosenthal DS. Sulfur Mustard Induces Apoptosis in Cultured Normal Human Airway Epithelial Cells: Evidence of a Dominant Caspase-8-mediated Pathway and Differential Cellular Responses*. Drug Chem Toxicol 2008;31(1):137-48.
10. Rosenthal DS, Simbulan‐Rosenthal CM, Iyer S, Smith WJ, Ray R, Smulson ME. Calmodulin, poly (ADP–ribose) polymerase and p53 are targets for modulating the effects of sulfur mustard. J Appl Toxicol 2000;20(Suppl 1):S43-9.
11. Rosenthal DS, Velena A, Chou F-P, Schlegel R, Ray R, Benton B, et al. Expression of dominant-negative Fas-associated death domain blocks human keratinocyte apoptosis and vesication induced by sulfur mustard. J Biol Chem 2003;278(10):8531-40.
12. Simbulan-Rosenthal CM, Ray R, Benton B, Soeda E, Daher A, Anderson D, et al. Calmodulin mediates sulfur mustard toxicity in human keratinocytes. Toxicology 2006;227(1):21-35.
13. Keyser BM, Andres DK, Nealley E, Holmes WW, Benton B, Paradiso D, et al. Postexposure Application of Fas Receptor Small-Interfering RNA to Suppress Sulfur Mustard–Induced Apoptosis in Human Airway Epithelial Cells: Implication for a Therapeutic Approach. J Pharmacol Exp Ther 2013;344(1):308-16.
14. Pirzad G, Jafari M, Tavana S, Sadrayee H, Ghavami S, Shajiei A, et al. The role of Fas-FasL signaling pathway in induction of apoptosis in patients with sulfur mustard-induced chronic bronchiolitis. J Toxicol 2011;2010:373612.
15. Rosenthal DS, Simbulan-Rosenthal CM, Iyer S, Spoonde A, Smith W, Ray R, et al. Sulfur Mustard Induces Markers of Terminal Differentiation and Apoptosis in Keratinocytes Via a Ca2+-Calmodulin and Caspase-Dependent Pathway. J Invest Dermatol 1998;111(1):64-71.
16. Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res2006;7(1):53.
17. Lu Q, Harrington EO, Rounds S. Apoptosis and lung injury. Keio J Med 2005;54(4):184-9.
18. Neff TA, Guo RF, Neff SB, Sarma JV, Speyer CL, Gao H, et al. Relationship of acute lung inflammatory injury to Fas/FasL system. Am J Pathol 2005;166(3):685-94.
19. Steinritz D, Emmler J, Hintz M, Worek F, Kreppel H, Szinicz L, et al. Apoptosis in sulfur mustard treated A549 cell cultures. Life Sci 2007;80(24-25):2199-201.
20. Ghazanfari T, Sharifnia Z, Yaraee R, Pourfarzam S, Kariminia A, Mahlojirad M, et al. Serum soluble Fas ligand and nitric oxide in long-term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study. Int Immunopharmacol 2009;9(13-14):1489-93.
21. Ray R, Simbulan-Rosenthal CM, Keyser BM, Benton B, Anderson D, Holmes W, et al. Sulfur mustard induces apoptosis in lung epithelial cells via a caspase amplification loop. Toxicology 2010;271(3):94-9.
22. Malaviya R, Sunil VR, Cervelli J, Anderson DR, Holmes WW, Conti ML, et al. Inflammatory effects of inhaled sulfur mustard in rat lung. Toxicol Appl Pharmacol 2010;248(2):89-99.
23. Kehe K, Reisinger H, Szinicz L. Sulfur mustard induces apoptosis and necrosis in SCL II cells in vitro. J Appl Toxicol 2000;20(S1):S81-S6.
24. Mol MA, van den Berg RM, Benschop HP. Involvement of caspases and transmembrane metalloproteases in sulphur mustard-induced microvesication in adult human skin in organ culture: directions for therapy. Toxicology 2009;258(1):39-46.
25. Shakarjian MP, Heck DE, Gray JP, Sinko PJ, Gordon MK, Casillas RP, et al. Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol Sci 2010;114(1):5-19.
26. Bröker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res 2005;11(9):3155-62.
27. Parrish AB, Freel CD, Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol 2013;5(6):a008672.
28. Willingham MC. Cytochemical methods for the detection of apoptosis. J Histochem Cytochem 1999;47(9):1101-9.

Files
IssueVol 15, No 4 (2016) QRcode
SectionOriginal Article(s)
Published2016-08-30
Keywords
Apoptosis Lung Lung disease Sulfur mustard

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Mosayebzadeh M, Ghazanfari T, Delshad A, Akbari H. Evaluation of Apoptosis in the Lung Tissue of Sulfur Mustard-exposed Individuals. Iran J Allergy Asthma Immunol. 15(4):283-288.