C5a受体颉颃剂及其在动物疾病模型治疗中的研究进展

中国畜牧兽医

C5a受体颉颃剂及其在动物疾病模型治疗中的研究进展

张泽英¹^,2，刘东旭²

（1.武汉生物工程学院食品工程系，湖北武汉 430015；2.湖北大学生命科学学院，湖北武汉 430062）

收稿日期:2013-08-09 出版日期:2014-02-20 发布日期:2014-03-27
通讯作者: 刘东旭（1962—），男，教授，博士生导师，研究方向：免疫与炎症。E-mail：dxl@hubei.edu.cn
作者简介:张泽英（1980—），女，四川人，硕士，讲师，研究方向：食品分析检测。
基金资助:
国家自然科学基金（31070776）。

Research Progress on C5a Receptor Antagonists and their Treatment in Animal Disease Model

ZHANG Ze-ying¹，2, LIU Dong-xu²

(1.Department of Food Engineering, Wuhan Bioengineering Institute, Wuhan 430015, China;2.School of Life Sciences, Hubei University, Wuhan 430062, China)

Received:2013-08-09 Online:2014-02-20 Published:2014-03-27

摘要/Abstract

摘要： C5a受体是人和动物体内补体系统的重要组成部分，与C5a结合后介导了众多生物学效应，参与了许多疾病的发生、发展，并在多种病变中起重要作用，如器官缺血再灌注损伤、急性肺损伤、脓毒血症、类风湿性关节炎、肾小球肾炎等疾病。如何抑制C5a受体的生物活性，从而减轻炎症反应一直是免疫学研究的热点问题。文章着重介绍了C5a受体颉颃剂及其在动物疾病模型治疗中的研究进展。

关键词: C5a; C5a受体; 颉颃剂; 补体; 治疗

Abstract: As a key part of the complement system in human and animal body, C5a receptor combined with C5a has been considered to mediate numerous biological processes and be involved in the pathology of numerous inflammatory diseases, such as ischemia-reperfusion injury, acute lung injury, sepsis, rheumatoid arthritis and glomerular nephritis．Therefore, current studies focus on how to block C5a receptor and dampen the inflammatory reaction. This review provides a brief overview of the current development of C5a receptor antagonists and their treatment in animal disease model.

Key words: C5a; C5a receptor; antagonists; complement; treatment

张泽英，刘东旭. C5a受体颉颃剂及其在动物疾病模型治疗中的研究进展[J]. 中国畜牧兽医.

ZHANG Ze-ying, LIU Dong-xu. Research Progress on C5a Receptor Antagonists and their Treatment in Animal Disease Model[J]. .

参考文献

1 王会会，陈国江，黎燕，等. 补体C5a、C5a受体及其拮抗剂的研究进展[J]. 国际药学研究杂志，2010，37(3)：181～186.
2 朱世明. C5a受体介导血管渗透性的机制[D]. 武汉：湖北大学，2010.
3 宋蓉，陈月，吕凤林，等. C5L2不再是孤儿受体——进展与展望[J]. 免疫学杂志，2007，23(2)：229～232.
4 陈月，吕凤林. 补体C5a新型抑制剂研究进展[J]. 中国免疫学杂志，2007，23(2)：180～184.
5 落智荣，帖菊霞，曹文斌，等. 念珠菌型小鼠乳房炎组织损伤程度与C3c补体激活水平相关性的研究[J]. 中国畜牧兽医，2007，34(1)：92～95.
6 Ager R, Fonseca M, Chu S, et al. Decreases in Alzheimer’s disease like pathology associated with C5aR inhibition correlate with improved performance in a passive avoidance task[J]. Molecular Immunology, 2008, 45(16): 4109.
7 Arumugam T V, Shiels I A, Woodruff T M, et al. Protective effect of a new C5a receptor antagonist against ischemia-reperfusion injury in the rat small intestine[J]. Surgical Research, 2002, 103(2): 260～267.
8 Arumugam T V, Woodruff T M, Shelli Z, et al. Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats[J]. Hepatology, 2004, 40(6): 934～941.
9 BeckK D, Nguyen H X, Galvan M D, et al. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: Evidence for amultiphasic inflammatory response in the acute to chronic environment[J]. Brain, 2010, 133(2): 433～447.
10 Blagg J, Mowbray C, Pryde D C, et al. Small, non-peptide C5a receptor antagonists: Part 1[J]. Bioorganic and Medicinal Chemistry Letters, 2008, 18(20): 5601～5604.
11 Boor P, Konieczny A, Villa L, et al. Complement C5 mediates experimental tubulointerstitial fibrosis[J]. American Society of Nephrology, 2007, 18(5): 1508～1515.
12 Brodbeck R M, Cortright D N, Kieltyka A P, et al. Identification and characterization of NDT 9513727[N, N-bis(1, 3-benzodioxol-5-ylmethyl)-1-butyl-2〖DK〗,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist[J]. Pharmacology and Experimental Therapeutics, 2008, 327(3): 898～909.
13 Bunschoten A, Ippel J H, Kruijtzer J A, et al. A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: Towards the development of novel anti-inflammatory compounds[J]. Amino Acids, 2011, 40(2): 731～740.
14 Garrett M C, Otten M L, Starke R M, et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage[J]. Brain Research, 2009, 1298: 171～177.
15 Hezmee M N, Kyaw-Tanner M, Lee J Y, et al. Increased expression of C5a receptor (CD88) mRNA in canine mammary tumors[J]. Veterinary Immunology and Immunopathology, 2011, 139(1): 50～56.
16 Hezmee M N, Shiels I A, Rolfe B E, et al. Complement C5a: Impact on the field of veterinary medicine[J]. Veterinary, 2012, 192(3): 264～271.
17 Huber-Lang M S, Riedeman N C, Sarma J V, et al. Protection of innate immunity by C5aR antagonist in septic mice[J]. FASEB, 2002, 16(12): 1567～1574.
18 Li K, Choudhry N, Peng Q, et al. C5a-C5aR interaction promotes kidney infection through acting on both renal and circulating cells[J]. Immunobiology, 2012, 217(11): 1145.
19 Li R, Coulthard L G, Wu M C. C5L2: A controversial receptor of complement anaphylatoxin, C5a[J]. FASEB, 2013, 27(3): 855～864.
20 Liang D Y, Li X Q, Shi X Y, et al. The complement component C5a receptor mediates pain and inflammation in a postsurgical pain model[J]. Pain, 2012, 153(2): 366～372.
21 Manthey H D, Thomas A C, Shiels I A, et al. Complement C5a inhibition reduces atherosclerosis in ApoE-/-mice[J]. FASEB Journal, 2011, 25(7): 2447～2455.
22 Peng Q, Li K, Wang N, et al. Dendritic cell function in allostimulation is modulated by C5aR signaling[J]. Immunology, 2009, 183(10): 6058～6068.
23 Peng Q, Xing G, Li K, et al. Double deficiency of C5aR/C3aR significantly prevents mice from renal ischemia/reperfusion injury[J]. Molecular Immunology, 2010, 47(13): 2235.
24 Qu H C, Ricklin D, Lambris J D. Recent developments in low molecular weight complement inhibitors[J]. Molecular Immunology, 2009, 47(2～3): 185～195.
25 Riley R D, Sato H, Zhao Z Q, et al. Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization[J]. Thoracic and Cardiovascular Surgery, 2000, 120(2): 350～358.
26 Schmudde I, Laumonnier Y, Strver H A, et al. C5a receptor signalling in dendritic cells regulates the development of maladaptive Th2 and Th17 immune responses in experimental allergic asthma[J]. Immunobiology, 2012, 217(11): 1145.
27 Schnatbaum K, Locardi E, Scharn D. Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: Increased receptor specificity and in vivo activity[J]. Bioorganic and Medicinal Chemistry Letters, 2006, 16(19): 5088～5092.
28 Shagdarsuren E, Bidzhekov K, Mause S F, et al. C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice[J]. Circulation, 2010, 122(10): 1026～1036.
29 van der Pals J, Koul S, Andersson P, et al. Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model[J]. BMC Cardiovascular Disorders, 2010, 10: 45.
30 Waters S M, Brodbeck R M, Steflik J, et al. Molecular characterization of the gerbil C5a receptor and identification of a transmembrane domain V amino acid that is crucial for small molecule antagonist interaction[J]. Biological Chemistry, 2005, 280(12): 40617～40623.
31 Woodruff T M, Strachan A J, Sanderson S D, et al. Species dependence for binding of small molecule agonist and antagonists to the C5a receptor on polymorphonuclear leukocytes[J]. Inflammation, 2001, 25(3): 171～177.
32 Woodruff T M, Strachan A J, Dryburgh N, et al. Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat[J]. Arthritis and Rheumatism, 2002, 46(9): 2476～2485.
33 Woodruff T M, Arumugam T V, Shiels I A. Protective effects of a potent C5a receptor antagonist on experimental acute lmb ischemia-reperfusion in rats[J]. Surgical Research, 2004, 116(1): 81～90.
34 Woodruff T M, Pollitt S, Proctor L M, et al. Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease[J]. Pharmacology and Experiment Therapeutics, 2005, 314(2): 811～817.
35 Woodruff T M, Ager R R, Tenner A J, et al. The role of the complement system and the activation fragment C5a in the central nervous system[J]. Neuromolecular Medicine, 2010, 12(2): 179～192.
36 Woodruff T M, Nandakumar K S, Tedesco F. Inhibiting the C5-C5a receptor axis[J]. Molecular Immunology, 2011, 48(14): 1631～1642.
37 Xiao H, Jennette J C, Dairaghi D, et al. Robust efficacy of C5aR antagonist CCX168 in a mouse model of ANCA glomerulonephritis[J]. American Society of Nephrology, 2010, 21: 40.

[1]	王超, 刘庚, 张林波. 地高辛标记核酸探针检测重组人白细胞介素1受体颉颃剂中DNA残余量的研究[J]. , 2013, 40(11): 54-58.
[2]	张海燕;;王长法;仲跻峰;杨桂文;安利国. 甘露糖结合凝集素相关的丝氨酸蛋白酶1研究进展[J]. , 2011, 38(1): 42-46.
[3]	落智荣;帖菊霞;曹文斌;王文魁. 念珠菌型小鼠乳房炎组织损伤程度与C3c补体激活水平相关性的研究[J]. , 2007, 34(1): 92-93.