SRT1720, a SIRT1 Activator, Aggravates Bleomycin-Induced Lung Injury in Mice

Shingo Imanishi, Ryuji Hayashi, Tomomi Ichikawa, Kensuke Suzuki, Masakiyo Sasahara, Takashi Kondo, Hirofumi Ogawa, Kazuyuki Tobe

Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan..
First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

DOI: 10.4236/fns.2012.32024                

Abstract

Diagnosis and management of interstitial lung diseases (ILDs), caused by lung epithelial injury followed by apoptosis, are often challenging. It has been controversial whether the SIRT1 protein, a principal modulator of longevity due to caloric restriction, ameliorates or aggravates ILD in animal models. Here we examined the effect of SRT1720, a syn- thetic activator of SIRT1, on bleomycin-induced lung injury in a mouse model and apoptosis in cultured epithelial cells. Oral intubation of SRT1720 over a period of 15 days caused body weight loss and a high mortality rate among bleomy- cin-treated mice. Histological examinations showed that the SRT1720 load increased fibrosis in the bleomycin-treated lung. An analysis of bronchoalveolar lavage fluid revealed remarkably increased numbers of inflammatory cells in the SRT1720-treated group. Moreover, the apoptosis of A549 lung cancer cells, caused by X-ray irradiation and an anti-Fas activating antibody, was promoted by SRT1720. These results indicate that SRT1720 not only aggravates bleomy- cin-induced ILD, but stimulates the apoptosis of physically and biologically stimulated A549 cells. While SIRT1 acti- vators are considered promising for the treatment of conditions such as diabetes mellitus, fatty liver, and chronic ob- structive pulmonary diseases, an excess of food containing SIRT1 activators may be harmful depending on the disease state, especially in the case of acute inflammation.

Keywords

Interstitial Lung Diseases (ILDs), Lung Injury; SIRT1, Bleomycin; X-Ray Irradiation; Oxidative Stress

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	O. J. Dempsey, K. M. Kerr, H. Remmen and A. R. Denison, “How to Investigate a Patient with Suspected Interstitial Lung Disease,” British Medical Journal, Vol. 340, 2010, p. c2843. doi:10.1136/bmj.c2843
[2]	O. Eickelberg and M. Selman, “Update in Diffuse ParenChymal Lung Disease 2009,” American Journal of Respiratory and Critical Care Medicine, Vol. 181, No. 9, 2010, pp. 883-888. doi:10.1164/rccm.201001-0124UP
[3]	L. E. Vanfleteren and C. F. Linssen, “Role of MicroorgaNisms in Interstitial Lung Disease,” Current Opinion in Pulmonary Medicine, Vol. 16, No. 5, 2010, pp. 489-495. doi:10.1097/MCP.0b013e32833b1c54
[4]	P. A. Wijnen, O. Bekers and M. Drent, “Relationship between Drug-Induced Interstitial Lung Diseases and CytoChrome p450 Polymorphisms,” Current Opinion in Pulmonary Medicine, Vol. 16, No. 5, 2010, pp. 496-502. doi:10.1097/MCP.0b013e32833c06f1
[5]	M. Chopra, J. S. Reuben and A. C. Sharma, “Acute Lung Injury, Apoptosis and Signaling Mechanisms,” Experimental Biology and Medicine, Vol. 234, No. 4, 2009, pp. 361371. doi:10.3181/0811-MR-318
[6]	A. Bast, A. R. Weseler, G. R. Haenen and G. J. den Hartog, “Oxidative Stress and Antioxidants in Interstitial Lung Disease,” Current Opinion in Pulmonary Medicine, Vol. 16, No. 5, 2010, pp. 516-520. doi:10.1097/MCP.0b013e32833c645d
[7]	J. W. Sam, S. Takahashi, I. Lippai, J. Peisach and D. L. Rousseau, “Sequence-Specific Changes in the Metal Site of Ferric Bleomycin Induced by the Binding of DNA,” Journal of Biological Chemistry, Vol. 273, No. 26, 1998, pp. 16090-16097. doi:10.1074/jbc.273.26.16090
[8]	J. Fukumoto, C. Harada, T. Kawaguchi, S. Suetsugu, T. Maeyama, I. Inoshima, N. Hamada, K. Kuwano and Y. Nakanishi, “Amphiregulin Attenuates Bleomycin-Induced Pneumopathy in Mice,” American Journal of Physiology —Lung Cellular and Molecular, Vol. 298, No. 2, 2010, pp. L131-138. doi:10.1152/ajplung.90576.2008
[9]	P. Camus, A. Fanton, P. Bonniaud, C. Camus and P. Foucher, “Interstitial Lung Disease Induced by Drugs and Radiation,” Respiration, Vol. 71, No. 4, 2004, pp. 301326. doi:10.1159/000079633
[10]	K. H. Lee and K. H. Rhee, “Radioprotective Effect of Cyclo(l-phenylalanyl-l-prolyl) on Irradiated Rat Lung,” Journal of Microbiology and Biotechnology, Vol. 18, No. 2, 2008, pp. 369-376.
[11]	B. Movsas, T. A. Raffin, A. H. Epstein and C. J. Link Jr., “Pulmonary Radiation Injury,” Chest, Vol. 111, No. 4, 1997, pp. 1061-1076. doi:10.1378/chest.111.4.1061
[12]	P. R. Graves, F. Siddiqui, M. S. Anscher and B. Movsas, “Radiation Pulmonary Toxicity. From Mechanisms to Management,” Seminars in Radiation Oncology, Vol. 20, No. 3, 2010, pp. 201-207. doi:10.1016/j.semradonc.2010.01.010
[13]	G. Blander and L. Guarente, “The Sir2 Family of Protein Deacetylases,” Annual Review of Biochemistry, Vol. 73, 2004, pp. 417-435.
[14]	L. Bordone and L. Guarente, “Calorie Restriction, Sirt1 and Metabolism. Understanding Longevity,” Nature Reviews Molecular Cell Biology, Vol. 6, No. 4, 2005, pp. 298-305. doi:10.1038/nrm1616
[15]	C. Cao, S. Lu, R. Kivlin, B. Wallin, E. Card, A. Bagdasarian, T. Tamakloe, W. J. Wang, X. Song, W. M. Chu, N. Kouttab, A. Xu and Y. Wan, “Sirt1 Confers Protection against Uvband h2o2-Induced Cell Death via Modulation of p53 and Jnk in Cultured Skin Keratinocytes,” Journal of Cellular and Molecular Medicine, Vol. 13, No. 96, 2009, pp. 3632-3643. doi:10.1111/j.1582-4934.2008.00453.x
[16]	K. Hasegawa, S. Wakino, K. Yoshioka, S. Tatematsu, Y. Hara, H. Minakuchi, K. Sueyasu, N. Washida, H. Tokuyama, M. Tzukerman, K. Skorecki, K. Hayashi and H. Itoh, “Kidney-Specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function,” Journal of Biological Chemistry, Vol. 285, No. 17, 2010, pp. 13045-13056. doi:10.1074/jbc.M109.067728
[17]	K. Ito, C. E. Charron and I. M. Adcock, “Impact of Protein Acetylation in Inflammatory Lung Diseases,” Pharmacology & Therapeutics, Vol. 116, No. 2, 2007, pp. 249-265. doi:10.1016/j.pharmthera.2007.06.009
[18]	J. T. Rodgers, C. Lerin, Z. Gerhart-Hines and P. Puigserver, “Metabolic Adaptations through the Pgc-1 Alpha and Sirt1 Pathways,” FEBS Letters, Vol. 582, No. 1, 2008, pp. 46-53.
[19]	J. H. Lim, Y. M. Lee, Y. S. Chun, J. Chen, J. E. Kim and J. W. Park, “Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1alpha,” Molecular Cell, Vol. 38, No. 6, 2010, pp. 864-878.
[20]	Z. Ungvari, N. Labinskyy, P. Mukhopadhyay, J. T. Pinto, Z. Bagi, P. Ballabh, C. Zhang, P. Pacher and A. Csiszar, “Resveratrol Attenuates Mitochondrial Oxidative Stress in Coronary Arterial Endothelial Cells,” American Journal of Physiology—Heart and Circulatory Physiology, Vol. 297, No. 5, 2009, pp. H1876-1881. doi:10.1152/ajpheart.00375.2009
[21]	S. R. Yang, J. Wright, M. Bauter, K. Seweryniak, A. Kode and I. Rahman, “Sirtuin Regulates Cigarette Smoke-Induced Proinflammatory Mediator Release via rela/ p65 nf-Kappab in Macrophages in Vitro and in Rat Lungs in Vivo, Implications for Chronic Inflammation and Aging,” American Journal of Physiology—Lung Cellular and Molecular, Vol. 292, No. 2, 2007, pp. L567-576.
[22]	S. R. Kim, K. S. Lee, S. J. Park, K. H. Min, Y. H. Choe, H. Moon, W. H. Yoo, H. J. Chae, M. K. Han and Y. C. Lee, “Involvement of Sirtuin 1 in Airway Inflammation and Hyperresponsiveness of Allergic Airway Disease,” Journal of Allergy and Clinical Immunology, Vol. 125, No. 2, 2010, pp. 449-460. doi:10.1016/j.jaci.2009.08.009
[23]	J. C. Milne, P. D. Lambert, S. Schenk, D. P. Carney, J. J. Smith, D. J. Gagne, L. Jin, O. Boss, R. B. Perni, C. B. Vu, J. E. Bemis, R. Xie, J. S. Disch, P. Y. Ng, J. J. Nunes, A. V. Lynch, H. Yang, H. Galonek, K. Israelian, W. Choy, A. Iffland, S. Lavu, O. Medvedik, D. A. Sinclair, J. M. Olefsky, M. R. Jirousek, P. J. Elliott and C. H. Westphal, “Small Molecule Activators of Sirt1 as Therapeutics for the Treatment of Type 2 Diabetes,” Nature, Vol. 450, No. 7170, 2007, pp. 712-716. doi:10.1038/nature06261
[24]	Y. Yamazaki, I. Usui, Y. Kanatani, Y. Matsuya, K. Tsuneyama, S. Fujisaka, A. Bukhari, H. Suzuki, S. Senda, S. Imanishi, K. Hirata, M. Ishiki, R. Hayashi, M. Urakaze, H. Nemoto, M. Kobayashi and K. Tobe, “Treatment with Srt1720, a Sirt1 Activator, Ameliorates Fatty Liver with Reduced Expression of Lipogenic Enzymes in Msg Mice,” American Journal of Physiology—Endocrinology and Metabolism, Vol. 297, No. 5, 2009, pp. E1179-E1186. doi:10.1152/ajpendo.90997.2008
[25]	T. Ashcroft, J. M. Simpson and V. Timbrell, “Simple Method of Estimating Severity of Pulmonary Fibrosis on a Numerical Scale,” Journal of Clinical Pathology, Vol. 41, No. 4, 1988, pp. 467-470. doi:10.1136/jcp.41.4.467
[26]	B. B. Moore and C. M. Hogaboam, “Murine Models of Pulmonary Fibrosis,” American Journal of Physiology— Lung Cellular and Molecular, Vol. 294, No. 2, 2008, pp. L152-160. doi:10.1152/ajplung.00313.2007
[27]	T. Fujita, M. Maruyama, J. Araya, K. Sassa, Y. Kawagishi, R. Hayashi, S. Matsui, T. Kashii, N. Yamashita, E. Sugiyama and M. Kobayashi, “Hydrogen Peroxide Induces Upregulation of Fas in Human Airway Epithelial Cells via the Activation of Parp-p53 Pathway,” American Journal of Respiratory Cell and Molecular Biology, Vol. 27, No. 5, 2002, pp. 542-552.
[28]	T. Yamada, M. Maruyama, T. Fujita, K. Miyabayashi, C. Shinoda, Y. Kawagishi, T. Fujishita, R. Hayashi, T. Miwa, N. Arai, S. Matsui, E. Sugiyama and M. Kobayashi, “Ionizing Radiation Suppresses Fap-1 Mrna Level in a549 Cells via p53 Activation,” FEBS Letters, Vol. 580, No. 18, 2006, pp. 4387-4391. doi:10.1016/j.febslet.2006.07.003
[29]	E. A. Sausville, J. Peisach and S. B. Horwitz, “A Role for Ferrous Ion and Oxygen in the Degradation of DNA by Bleomycin,” Biochemical and Biophysical Research Communications, Vol. 73, No. 3, 1976, pp. 814-822. doi:10.1016/0006-291X(76)90882-2
[30]	S. Chung, H. Yao, S. Caito, J. W. Hwang, G. Arunachalam and I. Rahman, “Regulation of SIRT1 in Cellular Functions: Role of Polyphenols,” Archives of Biochemistry and Biophysics, Vol. 501, No. 1, 2010, pp. 79-90. doi:10.1016/j.abb.2010.05.003
[31]	E. Maury, K. M. Ramsey and J. Bass, “Circadian Rhythms and Metabolic Syndrome: From Experimental Genetics to Human Disease,” Circulation Research, Vol. 106, No. 3, 2010, pp. 447-462. doi:10.1161/CIRCRESAHA.109.208355
[32]	Y. Lu, N. Azad, L. Wang, A. K. Iyer, V. Castranova, B. H. Jiang and Y. Rojanasakul, “Phosphatidylinositol-3-kinase/ akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production,” American Journal of Respiratory Cell and Molecular Biology, Vol. 42, No. 4, 2010, pp. 432-441. doi:10.1165/rcmb.2009-0002OC
[33]	G. Sener, N. Topaloglu, A. O. Sehirli, F. Ercan and N. Gedik, “Resveratrol Alleviates Bleomycin-Induced Lung Injury in Rats,” Pulmonary Pharmacology & Therapeutics, Vol. 20, No. 6, 2007, pp. 642-649. doi:10.1016/j.pupt.2006.07.003
[34]	K. R. Trott, T. Herrmann and M. Kasper, “Target Cells in Radiation Pneumopathy,” International Journal of Radiation Oncology Biology Physics, Vol. 58, No. 2, 2004, pp. 463-469. doi:10.1016/j.ijrobp.2003.09.045
[35]	J. E. Moulder and E. P. Cohen, “Future Strategies for Mitigation and Treatment of Chronic Radiation-Induced Normal Tissue Injury,” Seminars in Radiation Oncology, Vol. 17, No. 2, 2007, pp. 141-148. doi:10.1016/j.semradonc.2006.11.010
[36]	N. Hagimoto, K. Kuwano, H. Miyazaki, R. Kunitake, M. Fujita, M. Kawasaki, Y. Kaneko and N. Hara, “Induction of Apoptosis and Pulmonary Fibrosis in Mice in Response to Ligation of Fas Antigen,” American Journal of Respiratory Cell and Molecular Biology, Vol. 17, No. 3, 1997, pp. 272-278.
[37]	M. A. Sheard, B. Vojtesek, L. Janakova, J. Kovarik and J. Zaloudik, “Up-Regulation of Fas (CD95) in Human P53 wild-Type Cancer Cells Treated with Ionizing Radiation,” International Journal of Cancer, Vol. 73, No. 5, 1997, pp. 757-762. doi:10.1002/(SICI)1097-0215(19971127)73:5<757::AID-IJC24>3.0.CO;2-1
[38]	F. Yeung, J. E. Hoberg, C. S. Ramsey, M. D. Keller, D. R. Jones, R. A. Frye, M. W. Mayo, “Modulation of NF-BDependent Transcription and Cell Survival by the SIRT1 Deacetylase,” EMBO Journal, Vol. 23, No. 12, 2004, pp. 2369-2380.