Triptolide as an Alternative to IVIG Therapy for Kawasaki Disease in a Mouse Model

Yıl 2013, Cilt: 2013 Sayı: 2, 225 - 228, 01.02.2013

Zong-ting Yan Jian-wen Zou

https://doi.org/10.5152/balkanmedj.2013.7963

Öz

Background: Kawasaki disease is treated by immunoglobulin therapy, which has adverse side effects like renal damage. Aims: The aim of the present study was to explore the effectiveness of triptolide, a compound derived from threewingnut that has anti-inflammatory effects, on the treatment of Kawasaki disease in a mouse model. Study Design: Animal experiment. Methods: A mouse model of Kawasaki disease was established through exposure to Candida albicans by intraperitoneal injection. Exposed mice were then randomly divided into several groups (each n=15): model group (saline-treated), low- or high-dose triptolide groups (0.2 mg/kg or 0.4 mg/kg, respectively), and IVIG (high-dose immunoglobulin) group (1 g/kg body weight). Unexposed mice served as an additional control group. Nine weeks from the initial exposure, mice were euthanised and coronary tissues and blood samples were harvested. The rate of apoptosis was detected by TUNEL, and ICAM-1 expression was detected by immunohistochemistry in coronary endothelial cells. Serum TNF-α levels were detected by ELISA. Results: Compared to mice in the (unexposed) control group, apoptosis of endothelial cells, ICAM-1 expression, and serum TNF-α levels were significantly increased in all exposed mice (p<0.05), confirming the presence of disease. However, treatment with triptolide or IVIG significantly lowered these measures compared to untreated exposed mice (model group; p<0.05). Conclusions: Triptolide treatment reduces markers of coronary endothelial inflammation in a mouse model of Kawasaki disease, similar to IVIG treatment, and therefore may be a useful alternative therapy for this disease. Turkish Başlık: Kawasaki Hastalığı için Fare Modelinde IVIG Tedavisine Alternatif olarak Triptolid Tedavisi Anahtar Kelimeler: Triptolid, Kawasaki hastalığı, endotel hücreleri, apoptoz, ICAM-1, TNF-α Arka Plan: Kawasaki hastalığı, böbrek hasarı gibi olumsuz yan etkilere sahip immunoglobulin terapi ile tedavi edilmektedir. Amaç: Bu çalışmanın amacı, threewingnut adlı bitkiden türetilen ve anti-inflamatuar etkilere sahip bir bileşik olan triptolidin, Kawasaki hastalığının tedavisindeki etkinliğini fare modelinde araştırmaktı. Çalışma Tasarımı: Hayvan üzerinde deney. Yöntemler: İntraperitoneal Candida albicans enjeksiyonu ile Kawasaki hastalığının fare modeli oluşturuldu. Maruz bırakılan fareler daha sonra rasgele birkaç gruba ayrıldı (herbiri n=15): model grubu (salin ile muamele edilen), düşük veya yüksek doz triptolid grupları (sırasıyla 0.2 mg/kg veya 0.4 mg/kg) ve IVIG (yüksek doz immunoglobulin) grubu (1 g/kg vücut ağırlığı). Maruz bırakılmayan fareler ilave kontrol grubu olarak görev yaptı. İlk maruziyetten dokuz hafta sonra farelere ötenazi uygulandı ve koroner dokuları ve kan örnekleri alındı. Koroner endotel hücrelerinde apopitoz oranı TUNEL ile saptandı ve ICAM-1 ekspresyonu immunohistokimya ile saptandı. Serum TNF-α seviyeleri ELISA ile saptandı. Bulgular: Kontrol grubundaki farelere (maruz bırakılmamış) kıyasla, endotel hücrelerinin apopitozu, ICAM-1 ekspresyonu ve serum TNF-α seviyeleri maruz kalan tüm farelerde anlamlı şekilde artmıştı (p<0.05) ve bu da hastalık varlığını doğrulamaktaydı. Bununla birlikte triptolid veya IVIG tedavisi, maruz bırakılmış ve tedavi edilmemiş farelere kıyasla bu değerleri anlamlı şekilde düşürdü (model grubu; p<0.05). Sonuç: Triptolid tedavisi IVIG tedavisine benzer şekilde Kawasaki hastalığının fare modelinde koroner endoteliyal inflamasyonun belirteçlerini düşürmektedir ve dolayısıyla bu hastalık için yararlı bir alternatif tedavi olabilir.

Anahtar Kelimeler

Triptolide, Kawasaki disease, endothelial cells, apoptosis, ICAM-1, TNF-α

Triptolide as an Alternative to IVIG Therapy for Kawasaki Disease in a Mouse Model

Öz

Kaynakça

• Kim DS. Kawasaki disease. Yonsei Med J 2006;46:759-72. [CrossRef]
• Burns JC. The riddle of Kawasaki disease. N Engl J Med 2007;56:659-61. [CrossRef]
• Hui-Yuen JS, Duong TT, Yeung RS. TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease with coronary aneurysm in infant. J Immunol 2006;176:6294-301.
• Satou GM, Giamelli J, Gewitz MH. Kawasaki disease: diagnosis, management, and long-term implications. Cardiol Rev 2007;15:163-9. [CrossRef]
• Grunebaum E, Blank M, Cohen S, Afek A, Kopolovic J, Meroni PL, et al.The role of anti-endothelial cell antibodies in Kawasaki disease: in-vitro and in-vivo studies. Clin Exp Immunol 2002;130:233-40. [CrossRef]
• Leung DY, Cotran RS, Kurt-Jones E, Burns JC, Newburger JW, Pober JS. Endothelial activation in the pathogenesis of Kawasaki disease. Trans Assoc Am Physicians 1989;102:131-8.
• Furukawa S, Matsubara T, Jujoh K, Yone K, Sugawara T, Sasai K, et al. Peripheral blood monocyte/macrophages and serum tumor necrosis factor in Kawasaki disease. Clin Immunol Immunopathol 1988;48:247-51. [CrossRef]
• Lafferty TE, DeHoratius RJ, Smith JB. Aseptic meningitis as a side effect of intravenous immune gammaglobulin. J Rheumatol 1997;24:2491-2.
• Levy JB, Pusey CD. Nephrotoxicity of intravenous immunoglobulin. QJM 2000;93:751-5. [CrossRef]
• Gupta N, Ahmed I, Nissel-Horowitz S, Patel D, Mehrotra B. Intravenous gammaglobulin-associated acute renal failure. Am J Hemato 2001;66:151-2. [CrossRef]
• Liu MX, Dong J, Yang YJ, Yang XL, Xu HB. Progress in research on triptolide. Zhongguo Zhong Yao Za Zhi 2005;30:170-4.
• Lin KX, Wang CZ, Qian GS. Effects of triptolide on apoptosis of CD4+ and CD8 + T cells. Immunological J 2000;16:24-6.
• Wang HL, Yang YJ, He W, Tang DZ, Wang SJ. Effect of triptolide on cytotoxicity and NO production of activated mouse peritoneal macrophage. Zhonghua Yi Xue Za Zhi 2003;27:237-8.
• Nagi-Miura N, Harada T, Shinohara H, Kurihara K, Adachi Y, Ishida-Okawara A, et al. Lethal and severe coronary arteritis in DBA/2 mice induced by fungal pathogen, CAWS, Candida albicans water-soluble fraction. Atherosclerosis 2006;186:310-20. [CrossRef]
• Shinohara H, Nagi-Miura N, Ishibashi K, Adachi Y, Ishida-Okawara A, Oharaseki T, et al. Beta-mannosyl linkages negatively regulate anaphylaxis and vasculitis in mice, induced by CAWS, fungal PAMPS composed of mannoprotein-beta-glucan complex secreted by Candida albicans. Biol Pharm Bull 2006;29:1854-61. [CrossRef]
• Tsujimoto H, Takeshita S, Nakatani K, Kawamura Y, Tokutomi T, Sekine I. Delayed apoptosis of circulating neutrophils in Kawasaki disease. Clin Exp Immunol 2001;126:355-64. [CrossRef]
• Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, et al. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVlg involving the Fas apoptotic pathway. J Immunol 1998;161:3781-90.
• Leuenroth SJ, Bencivenga N, Chahboune H, Hyder F, Crews CM. Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD. Nephrol Dial Transplant 2010;25:21879 [CrossRef]
• Leuenroth SJ, Bencivenga N, Igarashi P, Somlo S,Crews CM. Triptolide reduces cystogenesis in a model of ADPKD. J Am Soc Nephrol 2008;19:1659-62. [CrossRef]
• Leuenroth SJ, Okuhara D, Shotwell JD, Markowitz GS, Yu Z, Somlo S, et al. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci USA 2007;104:4389-94. [CrossRef]
• Corson TW, Cavga H, Aberle N, Crews CM. Triptolide directly inhibits dCTP pyrophosphatase. Chembiochem 2011;12:1767-73. [CrossRef]
• Leuenroth SJ, Crews CM. Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure. Cancer Res 2008;68:5257-66. [CrossRef]