The Role of Progesterone in Cellular Apoptosis of Skin and Lung in a Bleomycin-injured Mouse Model
-
Fatemeh Vafashoar
,
Hadi Poormoghim
,
Kazem Mousavizadeh
,
Tahereh Mousavi Shabestari
,
Abbas Tavasoli
,
Seyed Ali Javadmoosavi
,
Nazanin Mojtabavi
Abstract
Systemic sclerosis is a female predominant, a fibrotic autoimmune disease in which disturbance in tissue homeostasis and cell turnover including cell apoptosis are central events in pathogenesis. Sex hormones are known as the important players in sexual dimorphism of autoimmune diseases and in tissue homeostasis. Progesterone influences autoimmune disease via its immunomodulatory effect or by its direct action on parenchymal cell function. On the other hand, this hormone impacts tissue homeostasis by acting on cell apoptosis in a different situation. The objective of this study was to examine the effect of progesterone on cellular apoptosis of skin and lung tissues in a mouse model of scleroderma. Four group of mice were involved in this study with 10 mice in each. The fibrotic model was induced by daily subcutaneous injection of bleomycin for 28 days. One week after initiation of fibrosis induction, mice received subcutaneous progesterone alone or with bleomycin for 21 days. Control group received only Phosphate buffered saline PBS. After 28 days, under lethal anesthesia skin and lung tissues were harvested for histological assessment and hydroxyproline measurement. Apoptosis in tissue sections was detected by TUNEL assay technique. Bleomycin administration induced fibrosis in skin and lung tissues. Severe apoptosis was seen in skin and lung tissues of the bleomycin-treated group (p<0.001 in the skin and p<0.05 in the lung). Progesterone injection either in the skin (p>0.05) or in the lung (p>0.05) did not alter apoptosis in bleomycin-treated animals. Our data confirm the role of apoptosis in the pathogenesis of fibrosis in this model; however, progesterone does not affect cellular apoptosis in skin and lung tissues of bleomycin-injured animals.
1. Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.
2. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nature reviews Molecular cell biology. 2008;9(3):231-41.
3. Kiess W, Gallaher B. Hormonal control of programmed cell death/apoptosis. European Journal of Endocrinology. 1998;138(5):482-91.
4. Medh RD, Thompson EB. Hormonal regulation of physiological cell turnover and apoptosis. Cell and tissue research. 2000;301(1):101-24.
5. Nagata S. Apoptosis and autoimmune diseases. Annals of the New York Academy of Sciences. 2010;1209(1):10-6.
6. Gallucci S, Caricchio R, Cohen PL. Cellular Injury and Apoptosis. The Autoimmune Diseases (Fifth Edition): Elsevier; 2014. p. 245-56.
7. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Physician. 2008;78(8):961-8.
8. Ho YY, Lagares D, Tager AM, Kapoor M. Fibrosis [mdash] a lethal component of systemic sclerosis. Nature Reviews Rheumatology. 2014;10(7):390-402.
9. Abraham D, Krieg T, Distler J, Distler O. Overview of pathogenesis of systemic sclerosis. Rheumatology. 2009;48(suppl_3):iii3-iii7.
10. Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Frontiers in immunology. 2015;6.
11. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. The Journal of clinical investigation. 2007;117(3):557.
12. Silman AJ. Epidemiology of scleroderma. Annals of the rheumatic diseases. 1991;50(Suppl 4):846.
13. Ackerman LS. Sex hormones and the genesis of autoimmunity. Archives of Dermatology. 2006;142(3):371-6.
14. Klein SL, Flanagan KL. Sex differences in immune responses. Nature Reviews Immunology. 2016;16(10):626-38.
15. Bhatia A, Sekhon HK, Kaur G. Sex hormones and immune dimorphism. The Scientific World Journal. 2014;2014.
16. Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Human reproduction update. 2005;11(4):411-23.
17. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nature Reviews Immunology. 2008;8(9):737-44.
18. Morrissy S, Xu B, Aguilar D, Zhang J, Chen QM. Inhibition of apoptosis by progesterone in cardiomyocytes. Aging cell. 2010;9(5):799-809.
19. Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Progress in brain research. 2009;175:219-37.
20. Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. Journal of Investigative Dermatology. 1999;112(4):456-62.
21. Hashimoto H, Eto T, Endo K, Itai G, Kamisako T, Suemizu H, et al. Comparative study of doses of exogenous progesterone administration needed to delay parturition in Jcl: MCH (ICR) mice. Experimental animals. 2010;59(4):521-4.
22. Jiang D, Liang J, Hodge J, Lu B, Zhu Z, Yu S, et al. Regulation of pulmonary fibrosis by chemokine receptor CXCR3. Journal of Clinical Investigation. 2004;114(2):291.
23. Wu M, Melichian DS, Chang E, Warner-Blankenship M, Ghosh AK, Varga J. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-γ. The American journal of pathology. 2009;174(2):519-33.
24. Alenzi FQ. Links between apoptosis, proliferation and the cell cycle. British journal of biomedical science. 2004;61(2):99-102.
25. Chabaud S, Moulin VJ. Apoptosis modulation as a promising target for treatment of systemic sclerosis. International journal of rheumatology. 2011;2011.
26. Jun J-B, Kuechle M, Harlan JM, Elkon KB. Fibroblast and endothelial apoptosis in systemic sclerosis. Current opinion in rheumatology. 2003;15(6):756-60.
27. Hoyles RK, Khan K, Shiwen X, Howat SL, Lindahl GE, Leoni P, et al. Fibroblast‐specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma‐associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model. Arthritis & Rheumatology. 2008;58(4):1175-88.
28. Laplante P, Raymond M-A, Gagnon G, Vigneault N, Sasseville AM-J, Langelier Y, et al. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. The Journal of Immunology. 2005;174(9):5740-9.
29. Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G. Endothelial cell apoptosis in systemic sclerosis is induced by antibody‐dependent cell‐mediated cytotoxicity via CD95. Arthritis & Rheumatology. 2000;43(11):2550-62.
30. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. Journal of Clinical Investigation. 1996;98(3):785.
31. Fanti S, Aloisi D, Dondi M, Marengo M, Compagnone G, Fallani F, et al. Early pulmonary involvement in systemic sclerosis assessed by technetium-99m-DTPA clearance rate. Journal of Nuclear Medicine. 1994;35(12):1933-6.
32. Barbas-Filho J, Ferreira M, Sesso A, Kairalla R, Carvalho C, Capelozzi V. Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). Journal of clinical pathology. 2001;54(2):132-8.
33. Wallach-Dayan SB, Izbicki G, Cohen PY, Gerstl-Golan R, Fine A, Breuer R. Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2006;290(4):L790-L6.
34. Mungunsukh O, Griffin AJ, Lee YH, Day RM. Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2010;298(5):L696-L703.
35. Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nature Reviews Immunology. 2014;14(3):166-80.
36. Ishrat T, Sayeed I, Atif F, Hua F, Stein DG. Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway. Neuroscience. 2012;210:442-50.
37. Grott M, Karakaya S, Mayer F, Baertling F, Beyer C, Kipp M, et al. Progesterone and estrogen prevent cisplatin-induced apoptosis of lung cancer cells. Anticancer research. 2013;33(3):791-800.
38. Syed V, Ho S-M. Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL. Oncogene. 2003;22(44):6883-90.
39. Nunes VA, Portioli-Sanches EP, Rosim M, Araujo M, Praxedes-Garcia P, Valle M, et al. Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism. Journal of Endocrinology. 2014;221(2):273-84.
40. Garrity MM, Burgart LJ, Riehle DL, Hill EM, Sebo TJ, Witzig T. Identifying and quantifying apoptosis: navigating technical pitfalls. Modern pathology. 2003;16(4):389-94.
| Files | ||
| Issue | Vol 18, No 1 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v18i1.635 | |
| Keywords | ||
| Apoptosis Bleomycin Progesterone Systemic sclerosis | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
