川崎病动物模型及其发病机制研究进展
The Development and Researches of the Pathogenesis of Kawasaki Disease Animal Models
DOI: 10.12677/JPS.2017.51001, PDF, HTML, XML, 下载: 2,571  浏览: 6,109  国家自然科学基金支持
作者: 张新艳*, 卢慧玲:华中科技大学同济医学院附属同济医院儿科,湖北 武汉
关键词: 川崎病动物模型免疫性血管炎发病机制免疫激活超抗原细胞因子Kawasaki Disease Animal Model Immune Vasculitis Pathogenesis Immune Activation Superantigen Cytokines
摘要: 川崎病(KD)随着发病率逐年增高,已经成为取代类风湿成为儿童后天性心脏病的主要病因。建立川崎病动物模型,对于其冠脉损伤病因及发病机制的研究至关重要,目前研究较多的有小鼠模型、兔模型、幼猪和犬模型,在动物模型的研究中发现单核/巨噬细胞的免疫激活、TNF-α和IL-1等细胞因子、基质金属蛋白酶(MMP-9)、血管内皮生长因-A(VEGF-A)、转化生长因子、TLR-2和MyD88及Dectin-1/Syk信号通路,均与川崎病模型中以冠状动脉损伤为主的免疫性血管炎有关。本文就目前运用川崎病免疫性血管炎模型研究其发病机制的现状进行总结概括。
Abstract: With the increasing morbidity of Kawasaki disease year by year, KD has become the main cause of acquired heart disease, which has replaced the rheumatoid disease. It’s vital to explore the etiology and pathogenesis of coronary artery lesions through establishing animal models of Kawasaki disease. At present, most researches focus on the mouse model, the rabbit model of immune vasculitis, young pig model and dog model, through which they found monocyte/macrophage activation, cytokines including TNF-α and IL-1, matrix metalloproteinases (MMP-9), vascular endothelial growth-A growth factors (VEGF-A), TLR-2 and MyD88 and Dectin-1/Syk signal pathway were all closely involved in the development of immune vasculitis in the KD animal models. In this paper, we summarize the latest development and researches of the pathogenesis of Kawasaki disease by using animal models of immune vasculitis.
文章引用:张新艳, 卢慧玲. 川崎病动物模型及其发病机制研究进展[J]. 生理学研究, 2017, 5(1): 1-11. https://doi.org/10.12677/JPS.2017.51001

参考文献

[1] Kawasaki, T. (1967) Acute Febrile Mucocutaneous Syndrome with Lymphoid Involvement with Specific Desquamation of the Fingers and Toes in Children. Allergy, 16, 178-222.
[2] Dajani, A.S., Taubert, K.A., Gerber, M.A., et al. (1993) Diagnosis and Therapy of Kawasaki Disease in Children. Circulation, 87, 1776-1780.
https://doi.org/10.1161/01.cir.87.5.1776
[3] Yoon, K.L. (2015) Update of Genetic Susceptibility in Patients with Kawasaki Disease. Korean Journal of Pediatrics, 58, 84.
https://doi.org/10.3345/kjp.2015.58.3.84
[4] Shulman, S.T. and Rowley, A.H. (2015) Kawasaki Disease: Insights into Pathogenesis and Approaches to Treatment. Nature Reviews Rheumatology, 11, 475-482.
https://doi.org/10.1038/nrrheum.2015.54
[5] Lehman, T.J., Allen, J.B., Plotz, P.H., et al. (1983) Polyarthritis in Rats Following the Systemic Injection of Lactobacillus Casei Cell Walls in Aqueous Suspension. Arthritis & Rheumatology, 26, 1259-1265.
https://doi.org/10.1002/art.1780261013
[6] Utsinger, P.D. (1980) Systemic Immune Complex Disease Following Intestinal Bypass Surgery: Bypass Disease. Journal of the American Academy of Dermatology, 2, 488-495.
https://doi.org/10.1016/S0190-9622(80)80149-6
[7] Cromartie, W.J. and Craddock, J.G. (1966) Rheumatic-Like Cardiac Lesions in Mice. Science, 154, 285-287.
https://doi.org/10.1126/science.154.3746.285
[8] Ohanian, S.H., Schwab, J.H. and Cromartie, W.J. (1969) Relation of Rheumatic-Like Cardiac Lesions of the Mouse to Localization of Group: A Streptococcal Cell Walls. The Journal of Experimental Medicine, 129, 37-49.
[9] Lehman, T.J., Walker, S.M., Mahnovski, V., et al. (1985) Coronary Arteritis in Mice Following the Systemic Injection of Group B Lactobacillus Casei Cell Walls in Aqueous Suspension. Arthritis & Rheumatology, 28, 652-659.
https://doi.org/10.1002/art.1780280609
[10] Lehman, T.J. and Mahnovski, V. (1988) Animal Models of Vasculitis. Lessons We Can Learn to Improve our Understanding of Kawasaki Disease. Rheumatic Diseases Clinics of North America, 14, 479-487.
[11] Lehman, T.J. (1993) Can We Prevent Long Term Cardiac Damage in Kawasaki Disease? Lessons from Lactobacillus Casei Cell Wall-Induced Arteritis in Mice. Clinical and Experimental Rheumatology, 11, 3-6.
[12] Rosenkranz, M.E., Schulte, D.J., Agle, LM., et al. (2005) TLR2 and MyD88 Contribute to Lactobacillus Casei Extract-Induced Focal Coronary Arteritis in a Mouse Model of Kawasaki Disease. Circulation, 112, 2966-2973.
[13] Lee, Y., Schulte, D.J., Shimada, K., et al. (2012) Interleukin-1 Is Crucial for the Induction of Coronary Artery Inflammation in a Mouse Model of Kawasaki Disease. Circulation, 125, 1542-1550.
https://doi.org/10.1161/CIRCULATIONAHA.111.072769
[14] Lau, A.C., Duong, T.T., Ito, S., et al. (2009) Inhibition of Matrix Metalloproteinase-9 Activity Improves Coronary Outcome in an Animal Model of Kawasaki Disease. Clinical & Experimental Immunology, 157, 300-309.
https://doi.org/10.1111/j.1365-2249.2009.03949.x
[15] Yuen, J.S., Duong, T.T. and Yeung, R.S. (2006) TNF-Alpha Is Necessary for Induction of Coronary Artery Inflammation and Aneurysm Formation in an Animal Model of Kawasaki Disease. The Journal of Immunology, 176, 6294-6301.
[16] Lin, I., Sheen, J., Tain, Y., et al. (2014) Vascular Endothelial Growth Factor: A in Lactobacillus Casei Cell Wall Extract-Induced Coronary Arteritis of a Murine Model. Circulation Journal, 78, 752-762.
[17] Lin, I.C., Kuo, H.C., Lin, Y.J., et al. (2012) Augmented TLR2 Expression on Monocytes in Both Human Kawasaki Disease and a Mouse Model of Coronary Arteritis. PLOS ONE, 7, Article ID: 38635.
https://doi.org/10.1371/journal.pone.0038635
[18] Murata, H. (1978) Experimental Arteritis on Murine with Candida—In Relation to Arteritis in MCLS. Kansenshogaku Zasshi, 52, 331-337.
https://doi.org/10.11150/kansenshogakuzasshi1970.52.331
[19] Murata, H. (1979) Experimental Candida-Induced Arteritis in Mice. Relation to Arteritis in the Mucocutaneous Lymph Node Syndrome. Microbiology and Immunology, 23, 825-831.
[20] Murata, H. and Naoe, S. (1987) Experimental Candida-Induced Arteritis in Mice-Relation to Arteritis in Kawasaki Disease. Progress in Clinical and Biological Research, 250, 523.
[21] Takahashi, K., Oharaseki, T., Wakayama, M., et al. (2004) Histopathological Features of Murine Systemic Vasculitis Caused by Candida Albicans Extract? An Animal Model of Kawasaki Disease. Inflammation Research, 53, 72-77.
[22] Oharaseki, T., Kameoka, Y., Kura, F., et al. (2005) Susceptibility Loci to Coronary Arteritis in Animal Model of Kawasaki Disease Induced with Candida Albicans-Derived Substances. Microbiology and Immunology, 49, 181-189.
[23] Onouchi, Z., Ikuta, K., Nagamatsu, K., et al. (1995) Coronary Artery Aneurysms Develop in Weanling Rabbits with Serum Sickness but Not in Mature Rabbits. An Experimental Model for Kawasaki Disease in Humans. Angiology, 46, 679-687.
https://doi.org/10.1177/000331979504600806
[24] 韦卫中, 陈绍军, 王宏伟, 等. 免疫性血管炎致冠状动脉损伤的实验研究[J]. 华中科技大学学报(医学版), 2004, 33(1): 41-44.
[25] Dou, J., Li, H., Sun, L., et al. (2013) Histopathological and Ultrastructural Examinations of Rabbit Coronary Artery Vasculitis Caused by Bovine Serum Albumin: An Animal Model of Kawasaki Disease. Ultrastructural Pathology, 37, 139-145.
https://doi.org/10.3109/01913123.2012.750409
[26] Philip, S., Lee, W., Liu, S., et al. (2004) A Swine Model of Horse Serum-Induced Coronary Vasculitis: An Implication for Kawasaki Disease. Pediatric Research, 55, 211-219.
https://doi.org/10.1203/01.PDR.0000104151.26375.E5
[27] Philip, S., Lee, W., Wu, M., et al. (2014) Histopathological Evaluation of Horse Serum-Induced Immune Complex Vasculitis in Swine: Implication to Coronary Artery Lesions in Kawasaki Disease. Pediatrics & Neonatology, 55, 297- 305.
https://doi.org/10.1016/j.pedneo.2013.10.012
[28] Burns, J.C., Felsburg, P. J., Wilson, H., et al. (1991) Canine Pain Syndrome Is a Model for the Study of Kawasaki Disease. Perspectives in Biology and Medicine, 35, 68-73.
https://doi.org/10.1353/pbm.1991.0040
[29] Felsburg, P.J., HogenEsch, H., Somberg, R.L., et al. (1992) Immunologic Abnormalities in Canine Juvenile Polyarteritis Syndrome: A Naturally Occurring Animal Model of Kawasaki Disease. Clinical Immunology and Immunopathology, 65, 110-118.
https://doi.org/10.1016/0090-1229(92)90213-8
[30] Schulte, D.J., Yilmaz, A., Shimada, K., et al. (2009) Involvement of Innate and Adaptive Immunity in a Murine Model of Coronary Arteritis Mimicking Kawasaki Disease. The Journal of Immunology, 183, 5311-5318.
[31] Orenstein, J.M., Shulman, S.T., Fox, L.M., et al. (2012) Three Linked Vasculopathic Processes Characterize Kawasaki Disease: A Light and Transmission Electron Microscopic Study. PLOS ONE, 7, Article ID: 38998.
https://doi.org/10.1371/journal.pone.0038998
[32] Sahr, A., Former, S., Hildebrand, D., et al. (2015) T-Cell Activation or Tolerization: The Yin and Yang of Bacterial Superantigens. Frontiers in Microbiology, 6, 1153.
https://doi.org/10.3389/fmicb.2015.01153
[33] Abe, J., Kotzin, B.L., Jujo, K., et al. (1992) Selective Expansion of T Cells Expressing T-Cell Receptor Variable Regions V Beta 2 and V Beta 8 in Kawasaki Disease. Proceedings of the National Academy of Sciences, 89, 4066-4070.
[34] Abe, J., Kotzin, B.L., Meissner, C., et al. (1993) Characterization of T-Cell Repertoire Changes in Acute Kawasaki Disease. Journal of Experimental Medicine, 177, 791-796.
https://doi.org/10.1084/jem.177.3.791
[35] Duong, T.T., Silverman, E.D., Bissessar, M.V., et al. (2003) Super Antigenic Activity Is Responsible for Induction of Coronary Arteritis in Mice: An Animal Model of Kawasaki Disease. International Immunology, 15, 79-89.
https://doi.org/10.1093/intimm/dxg007
[36] Kalliolias, G.D. and Ivashkiv, L.B. (2016) TNF Biology, Pathogenic Mechanisms and Emerging Therapeutic Strategies. Nature Reviews Rheumatology, 12, 49-62.
https://doi.org/10.1038/nrrheum.2015.169
[37] Chien, Y.H., Chang, K., Yang, Y.H., et al. (2003) Association between Levels of TNF-Alpha and TNF-Alpha Promoter-308 A/A Polymorphism in Children with Kawasaki Disease. Journal of the Formosan Medical Association, 102, 147-150.
[38] Ma, L. and Du, Z.D. (2016) Advances in the Pathogenesis of Vascular Endothelial Cells Injury in Kawasaki Disease. Chinese Journal of Pediatrics, 54, 158-160.
[39] Sakata, K., Hamaoka, K., Ozawa, S., et al. (2010) Matrix Metalloproteinase-9 in Vascular Lesions and Endothelial Regulation in Kawasaki Disease. Official Journal of the Japanese Circulation Society, 74, 1670-1675.
https://doi.org/10.1253/circj.CJ-09-0980
[40] 张艳兰, 杜忠东, 杨海明, 等. 川崎病小鼠肿瘤坏死因子α/核因子κB/基质金属蛋白酶-9通路研究[J]. 中国循证儿科杂志, 2014, 9(1), 59-63.
[41] Oharaseki, T., Yokouchi, Y., Yamada, H., et al. (2013) The Role of TNF-α in a Murine Model of Kawasaki Disease Arteritis Induced with a Candida Albicans Cell Wall Polysaccharide. Modern Rheumatology, 24, 120-128.
https://doi.org/10.3109/14397595.2013.854061
[42] Jiang, C., Fang, X., Jiang, Y., et al. (2016) TNF-α Induces Vascular Endothelial Cells Apoptosis through Overexpressing Pregnancy Induced Noncoding RNA in Kawasaki Disease Model. The International Journal of Biochemistry & Cell Biology, 72, 118-124.
https://doi.org/10.1016/j.biocel.2016.01.011
[43] Lee, Y., Wakita, D., Dagvadorj, J., et al. (2015) IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model Significance. Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 2605-2616.
[44] Wakita, D., Kurashima, Y., Crother, T.R., et al. (2016) Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease-Associated Abdominal Aortic Aneurysm. Arteriosclerosis, Thrombosis, and Vascular Biology, 36, 886-897.
https://doi.org/10.1161/ATVBAHA.115.307072
[45] Miyamoto, K., Yamazaki, Y., Okamoto, K., et al. (2013) Kawasaki Disease: Relationship between Acute Surgical Abdomen and Cytokine Profiles. The Pediatric Infectious Disease Journal, 32, 1299.
https://doi.org/10.1097/INF.0b013e31829ece3d
[46] Fury, W., Tremoulet, A.H., Watson, V.E., et al. (2010) Transcript Abundance Patterns in Kawasaki Disease Patients with Intravenous Immunoglobulin Resistance. Human Immunology, 71, 865-873.
https://doi.org/10.1016/j.humimm.2010.06.008
[47] Chan, W.C., Duong, T.T. and Yeung, R.S.M. (2004) Presence of IFN-Does Not Indicate Its Necessity for Induction of Coronary Arteritis in an Animal Model of Kawasaki Disease. The Journal of Immunology, 173, 3492-3503.
https://doi.org/10.4049/jimmunol.173.5.3492
[48] Muvva, C., Patra, S. and Venkatesan, S. (2016) MMPI: A Wide Range of Available Compounds of Matrix Metalloproteinase Inhibitors. PLOS ONE, 11, Article ID: 159321.
[49] Kurzepa, J., El-Demerdash, F.M. and Castellazzi, M. (2016) Matrix Metalloproteinases as a Pleiotropic Biomarker in Medicine and Biology. Disease Markers, 2016, Article ID: 9275204.
[50] Tscheuschler, A., Meffert, P., Beyersdorf, F., et al. (2016) MMP-2 Isoforms in Aortic Tissue and Serum of Patients with Ascending Aortic Aneurysms and Aortic Root Aneurysms. PLOS ONE, 11, Article ID: 164308.
https://doi.org/10.1371/journal.pone.0164308
[51] Lau, A.C., Rosenberg, H., Duong, T.T., et al. (2007) Elastolytic Matrix Metalloproteinases and Coronary Outcome in Children with Kawasaki Disease. Pediatric Research, 61, 710-715.
https://doi.org/10.1203/pdr.0b013e318053418b
[52] Lau, A.C., Duong, T.T., Ito, S., et al. (2008) Matrix Metalloproteinase 9 Activity Leads to Elastin Breakdown in an Animal Model of Kawasaki Disease. Arthritis & Rheumatism, 58, 854-863.
https://doi.org/10.1002/art.23225
[53] Gavin, P.J., Crawford, S.E., Shulman, S.T., et al. (2003) Systemic Arterial Expression of Matrix Metalloproteinases 2 and 9 in Acute Kawasaki Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 576-581.
[54] Korematsu, S., Ohta, Y., Tamai, N., et al. (2012) Cell Distribution Differences of Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Patients with Kawasaki Disease. The Pediatric Infectious Disease Journal, 31, 973-974.
https://doi.org/10.1097/INF.0b013e31825ba6b3
[55] Szatmary, Z. (2012) Molecular Biology of Toll-Like Receptors. General Physiology and Biophysics, 31, 357-366.
[56] Duffy, L. and O'Reilly, S.C. (2016) Toll-Like Receptors in the Pathogenesis of Autoimmune Diseases: Recent and Emerging Translational Developments. ImmunoTargets and Therapy, 5, 69-80.
https://doi.org/10.2147/ITT.S89795
[57] Joosten, L.A., Abdollahi-Roodsaz, S., Dinarello, C.A., et al. (2016) Toll-Like Receptors and Chronic Inflammation in Rheumatic Diseases: New Developments. Nature Reviews Rheumatology, 12, 344-357.
[58] Lin, J., Kakkar, V. and Lu, X. (2016) Essential Roles of Toll-Like Receptors in Atherosclerosis. Current Medicinal Chemistry, 23, 431-454.
https://doi.org/10.2174/0929867323666151207111408
[59] Krogmann, A.O., Lusebrink, E., Steinmetz, M., et al. (2016) Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CPG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice. PLOS ONE, 11, Article ID: 146326.
https://doi.org/10.1371/journal.pone.0146326
[60] Michelsen, K.S., Wong, M.H., Shah, P.K., et al. (2004) Lack Of Toll-Like Receptor 4 or Myeloid Differentiation Factor 88 Reduces Atherosclerosis and Alters Plaque Phenotype in Mice Deficient in Apolipoprotein E. Proceedings of the National Academy of Sciences, 101, 10679-10684.
https://doi.org/10.1073/pnas.0403249101
[61] Lu, Z., Zhang, X., Li, Y., et al. (2013) TLR4 Antagonist Reduces Early-Stage Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice. Journal of Endocrinology, 216, 61-71.
https://doi.org/10.1530/JOE-12-0338
[62] Alvira, C.M., Guignabert, C., Kim, Y., et al. (2011) Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease. The American Journal of Pathology, 178, 1210-1220.
https://doi.org/10.1016/j.ajpath.2010.11.054
[63] Lin, I., Suen, J., Huang, S., et al. (2013) Dectin-1/Syk Signaling Is Involved in Lactobacillus Casei Cell Wall Extract-Induced Mouse Model of Kawasaki Disease. Immunobiology, 218, 201-212.
[64] Hamaoka-Okamoto, A., Suzuki, C., Yahata, T., et al. (2014) The Involvement of the Vasa Vasorum in the Development of Vasculitis in Animal Model of Kawasaki Disease. Pediatric Rheumatology Online Journal, 12, 12.
[65] Nakamura, A., Okigaki, M., Miura, N., et al. (2014) Involvement of Mannose-Binding Lectin in the Pathogenesis of Kawasaki Disease-Like Murine Vasculitis. Clinical Immunology, 153, 64-72.
https://doi.org/10.1016/j.clim.2014.03.019
[66] Yoshikane, Y., Koga, M., Imanaka-Yoshida, K., et al. (2015) JNK Is Critical for the Development of Candida Albicans-Induced Vascular Lesions in a Mouse Model of Kawasaki Disease. Cardiovascular Pathology, 24, 33-40.
https://doi.org/10.1016/j.carpath.2014.08.005
[67] Chen, S., Lee, Y., Crother, T.R., et al. (2012) Marked Acceleration of Atherosclerosis after Lactobacillus Casei-Induced Coronary Arteritis in a Mouse Model of Kawasaki Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 60-71.
https://doi.org/10.1161/ATVBAHA.112.249417
[68] Stock, A.T., Hansen, J.A., Sleeman, M.A., et al. (2016) GM-CSF Primes Cardiac Inflammation in a Mouse Model of Kawasaki Disease. The Journal of Experimental Medicine, 213, 1983-1998.
https://doi.org/10.1084/jem.20151853
[69] Takahashi, K., Oharaseki, T., Yokouchi, Y., et al. (2010) Administration of Human Immunoglobulin Suppresses Development of Murine Systemic Vasculitis Induced with Candida Albicans Water-Soluble Fraction: An Animal Model of Kawasaki Disease. Modern Rheumatology, 20, 160-167.
https://doi.org/10.3109/s10165-009-0250-5