综述
基质金属蛋白酶-9抑制剂与炎症性肠病的研究进展
中华炎性肠病杂志, 2019,03(1) : 90-92. DOI: 10.3760/cma.j.issn.2096-367X.2019.01.019
摘要

基质金属蛋白酶-9(MMP-9)是降解细胞外基质的最主要的一种基质金属蛋白酶,其在炎症性肠病(IBD)的发生发展中起着重要的作用。MMP-9抑制剂近年来也成为IBD治疗的研究热点。动物研究显示许多动植物成分及合成药物可有效抑制MMP-9的表达,而免疫抑制药物是目前唯一临床应用有效的MMP-9抑制剂,却仍存在许多不良反应,关于MMP-9升高是IBD的结果还是原因尚无定论,因而MMP-9特异性抗体治疗IBD的可行性和有效性尚未明确。

引用本文: 孙晓伟, 魏娟, 汪芳裕. 基质金属蛋白酶-9抑制剂与炎症性肠病的研究进展 [J] . 中华炎性肠病杂志, 2019, 03(1) : 90-92. DOI: 10.3760/cma.j.issn.2096-367X.2019.01.019.
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基质金属蛋白酶(matrix metalloproteinases,MMP)是一类分解细胞外基质(ECM)的肽链内切酶,主要由上皮细胞、间质细胞和白细胞分泌,因其催化结构域活化需结合一个锌离子而得名。根据作用域结构和作用底物的不同,可以分为胶原酶(MMP-1、MMP-8、MMP-13、MMP-18)、明胶酶(MMP-2、MMP-9)、间质溶解素(MMP-3、MMP-10、MMP-11、MMP-12、MMP-16)和膜型金属蛋白酶(MT-MMP-1、MT-MMP-2)。MMP与基质金属蛋白酶抑制剂(tissue inhibitors of metalloproteinases,TIMP)之间的平衡是维持肠道黏膜正常生理功能的基础[1]。正常条件下MMP的活性很低,而在组织修复或炎症反应状态下,二者失衡,MMP活性升高[2]

MMP-9是一种来源于结肠上皮细胞、巨噬细胞和中性粒细胞的明胶酶,主要参与降解细胞外基质中的IV型胶原。在众多MMP中,MMP-9在肠道组织外基质的降解中起着关键性的作用,随着人们认识的深入,其在炎症反应中的调节免疫、血管生成、破坏上皮细胞屏障及黏液屏障、介导肠道纤维化等功能得以揭示[3]。抑制MMP-9也成为炎症性肠病(inflammatory bowel disease,IBD)潜在的治疗靶点[4]。MMP-9抑制剂可分为天然抑制剂和合成抑制剂。我们回顾和评价近年来针对MMP-9抑制剂和IBD治疗策略之间关系的研究成果并作进一步的展望。

一、MMP-9天然抑制剂

TIMP是人体内天然抑制剂,其与MMP之间的动态平衡维持着细胞屏障的稳定,其本应成为理想的抑制剂,但研究发现TIMP除了特异性地抑制MMP之外,还可以发挥类细胞因子作用与靶细胞膜受体结合从而调节细胞增殖凋亡和血管生成等其他作用,因此使用TIMP治疗容易产生促进肿瘤增殖转移等不良反应[5]

动物研究表明,天然抑制剂如许多动植物成分可以通过抑制MMP-9的表达而缓解结肠炎症反应[6,7,8,9],同时,食物中的膳食钙及内源性多不饱和脂肪酸也可以起到相似的抑制剂作用[10,11,12]

二、MMP-9合成抑制剂

在合成抑制剂中,巴比妥类药物可以抑制MMP-9的表达,减轻结肠炎症反应[13];在此基础上加入一氧化氮(NO)基团能增强其抑制效率并减少不良反应[14,15,16]。多西环素可以非选择性抑制MMP-9表达。RO28-2653不仅抑制特异性强、效率更高,而且可以防止炎性大肠杆菌的过度生长[17,18]

免疫抑制药物,包括激素、硫唑嘌呤、甲氨蝶呤及肿瘤坏死因子(tumor necrosis factor,TNF)-α抗体等,是目前应用于临床的合成抑制剂。在英夫利西单克隆抗体治疗克罗恩病(Crohn′s disease,CD)患者的体内外试验中,英夫利西单克隆抗体可以通过拮抗TNF-α减少MMP-9的分泌,减少分泌MMP-9的炎性细胞(中性粒细胞、单核细胞/巨噬细胞),通过降低TNF-α、MMP-9、MMP-11的水平和促进炎性细胞的凋亡而防止IBD的癌变[19]。糖皮质激素、硫唑嘌呤和甲氨蝶呤也同样可以抑制CD患者炎性细胞分泌MMP-9[20]

抗MMP-9抗体是目前靶向治疗研究的热点。许多动物研究表明,敲除MMP-9基因或使用抗MMP-9抗体可以有效缓解小鼠结肠炎[21,22,23,24]。非选择性MMP抗体可引起类似肌腱炎表现,出现纤维肌痛或肌肉骨骼综合征(musculoskeletal syndrome,MSS)等不良反应,但高选择性抗体避免了这些问题[25,26]。在IBD患者中,有报道称抗MMP-9抗体CALY-001可以防止CD患者肠道的狭窄和瘘管形成[27]。抗MMP-9抗体GS-5745治疗中重度溃疡性结肠炎(ulcerative colitis,UC)患者的Ⅰ期临床随机对照试验结果表明,GS-5745可以促进UC患者临床、内镜及组织学上的好转,且无不良事件发生[28]。但该研究团队在进行8周的Ⅱ/Ⅲ期临床试验后发现GS-5745不能促进中重度UC的临床缓解,遂终止试验[29]。Bruyn等[30]观察到敲除MMP-9基因或抑制MMP-9不能缓解肠道炎症反应,认为MMP-9水平的升高是肠道炎症反应的结果而非病因。关于抗MMP-9抗体在IBD患者中的作用机制及有效性、安全性仍有待进一步的探索。

三、结论

MMP-9作为IBD病情发展中的关键MMP,是潜在的治疗靶点,已得到广泛的研究。许多动植物提取物及合成药物在动物实验中可有效抑制MMP-9,但其临床应用前景尚不明确。免疫抑制药物是目前唯一临床应用有效的MMP-9抑制剂,却仍存在较多不良反应,因而MMP-9特异性抗体成为新的研究热点,然而MMP-9升高与肠道炎症反应何者为始发因素尚无定论,这也是当前MMP-9抗体研究过程中亟需解决的问题。

参考文献
[1]
LambertE, DasseE, HayeB, et al. TIMPs as multifacial proteins[J]. Crit Rev Oncol Hematol, 2004, 49(3): 187-198. DOI: 10.1016/j.critrevonc.2003.09.008.
[2]
BonnansC, ChouJ, WerbZ. Remodelling the extracellular matrix in development and disease[J]. Nat Rev Mol Cell Biol, 2014, 15(12): 786-801. DOI: 10.1038/nrm3904.
[3]
O′SullivanS, GilmerJF, MedinaC. Matrix metalloproteinases in inflammatory bowel disease:an update[J]. Mediators Inflamm, 2015, 2015(11): 964131. DOI: 10.1155/2015/964131.
[4]
RaviA, GargP, SitaramanSV. Matrix metalloproteinases in inflammatory bowel disease:boon or a bane?[J]. Inflamm Bowel Dis, 2007, 13(1): 97-107. DOI: 10.1002/ibd.20011.
[5]
ChircoR, LiuXW, JungKK, et al. Novel functions of TIMPs in cell signaling[J]. Cancer Metastasis Rev, 2006, 25(1): 99-113. DOI: 10.1007/s10555-006-7893-x.
[6]
di PaolaR, EspositoE, MazzonE, et al. Teupolioside, a phenylpropanoid glycosides of Ajuga reptans, biotechnologically produced by IRBN22 plant cell line, exerts beneficial effects on a rodent model of colitis[J]. Biochem Pharmacol, 2009, 77(5): 845-857. DOI: 10.1016/j.bcp.2008.11.010.
[7]
MazzonE, EspositoE, di PaolaR, et al. Effects of verbascoside biotechnologically produced by Syringa vulgaris plant cell cultures in a rodent model of colitis[J]. Naunyn Schmiedebergs Arch Pharmacol, 2009, 380(1): 79-94. DOI: 10.1007/s00210-009-0400-5.
[8]
MaoJW, HeXM, TangHY, et al. Protective role of metallopro-teinase inhibitor(AE-941)on ulcerative colitis in rats[J]. World J Gastroenterol, 2012, 18(47): 7063-7069. DOI: 10.3748/wjg.v18.i47.7063.
[9]
TrivediPP, JenaGB. Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice:studies on inflammation, oxidative stress, DNA damage and fibrosis[J]. Food Chem Toxicol, 2013, 59: 339-355. DOI: 10.1016/j.fct.2013.06.019.
[10]
SchepensM, SchonewilleAJ, VinkC, et al. Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats[J]. J Nutr, 2009, 139(8): 1525-1533. DOI: 10.3945/jn.109.105205.
[11]
BertonA, RigotV, HuetE, et al. Involvement of fibronectin type II repeats in the efficient inhibition of gelatinases A and B by long-chain unsaturated fatty acids[J]. J Biol Chem, 2001, 276(23): 20458-20465. DOI: 10.1074/jbc.M011664200.
[12]
GravaghiC, la PerleKM, OgrodwskiP, et al. Cox-2 expression, PGE(2)and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice[J]. J Nutr Biochem, 2011, 22(4): 360-365. DOI: 10.1016/j.jnutbio.2010.03.003.
[13]
GramsF, BrandstetterH, D′AloS, et al. Pyrimidine-2, 4, 6-Triones:a new effective and selective class of matrix metallopro-teinase inhibitors[J]. Biol Chem, 2001, 382(8): 1277-1285. DOI: 10.1515/BC.2001.159.
[14]
O′SullivanS, MedinaC, LedwidgeM, et al. Nitric oxide-matrix metaloproteinase-9 interactions:biological and pharmacological significance--NO and MMP-9 interactions[J]. Biochim Biophys Acta, 2014, 1843(3): 603-617. DOI: 10.1016/j.bbamcr.2013.12.006.
[15]
WangJ, O′SullivanS, HarmonS, et al. Design of barbiturate-nitrate hybrids that inhibit MMP-9 activity and secretion[J]. J Med Chem, 2012, 55(5): 2154-2162. DOI: 10.1021/jm201352k.
[16]
O′SullivanS, WangJ, PigottMT, et al. Inhibition of matrix metalloproteinase-9 by a barbiturate-nitrate hybrid ameliorates dextran sulphate sodium-induced colitis:effect on inflammation-related genes[J]. Br J Pharmacol, 2017, 174(7): 512-524. DOI: 10.1111/bph.13712.
[17]
HuangTY, ChuHC, LinYL, et al. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases[J]. Toxicol Appl Pharmacol, 2009, 237(1): 69-82. DOI: 10.1016/j.taap.2009.02.026
[18]
HeimesaatMM, DunayIR, FuchsD, et al. Selective gelatinase blockage ameliorates acute DSS colitis[J]. Eur J Microbiol Immunol(Bp), 2011, 1(3): 228-236. DOI: 10.1556/EuJMI.1.2011.3.7.
[19]
KimYJ, HongKS, ChungJW, et al. Prevention of colitis-associated carcinogenesis with infliximab[J]. Cancer Prev Res (Phila), 2010, 3(10): 1314-1333. DOI: 10.1158/1940-6207.CAPR-09-0272.
[20]
MakitaloL, SipponenT, KarkkainenP, et al. Changes in matrix metalloproteinase(MMP)and tissue inhibitors of metalloproteinases(TIMP)expression profile in Crohn′s disease after immunosuppressive treatment correlate with histological score and calprotectin values[J]. Int J Colorectal Dis, 2009, 24(10): 1157-1167. DOI: 10.1007/s00384-009-0756-50.
[21]
CastanedaFE, WaliaB, Vijay-KumarM, et al. Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice:central role of epithelial-derived MMP[J]. Gastroenterology, 2005, 129(6): 1991-2008. DOI: 10.1053/j.gastro.2005.09.017.
[22]
Sela-PasswellN, KikkeriR, DymO, et al. Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential[J]. Nat Med, 2011, 18(1): 143-147. DOI: 10.1038/nm.2582.
[23]
MarshallDC, LymanSK, McCauleyS, et al. Selective allosteric inhibition of MMP-9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer[J]. PLoS One, 2015, 10(5): e127063. DOI: 10.1371/journal.pone.0127063.
[24]
GargP, Vijay-KumarM, WangL, et al. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis[J]. Am J Physiol Gastrointest Liver Physiol, 2009, 296(2): G175-G184. DOI: 10.1152/ajpgi.90454.2008.
[25]
CoussensLM, FingletonB, MatrisianLM. Matrix metalloproteinase inhibitors and cancer:trials and tribulations[J]. Science, 2002, 295(5564): 2387-2392. DOI: 10.1126/science.1067100.
[26]
PetersonJT. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors[J]. Cardiovasc Res, 2006, 69(3): 677-687. DOI: 10.1016/j.cardiores.2005.11.032.
[27]
GoffinL, FagagniniS, VicariA, et al. Anti-MMP-9 antibody:a promising therapeutic strategy for treatment of inflammatory bowel disease complications with fibrosis[J]. Inflamm Bowel Dis, 2016, 22(9): 2041-2057. DOI: 10.1097/MIB.0000000000000863.
[28]
SandbornWJ, BhandariBR, FogelR, et al. Randomised clinical trial:a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis[J]. Aliment Pharmacol Ther, 2016, 44(2): 157-169. DOI: 10.1111/apt.13653.
[29]
SandbornWJ, BhandariBR, RandallC, et al. Andecaliximab [anti-matrix metalloproteinase-9] induction therapy for ulcerative colitis:a randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease[J]. J Crohns Colitis, 2018. DOI: 10.1093/ecco-jcc/jjy049.[Epub ahead of print]
[30]
BruynMD, BreynaertC, ArijsI, et al. Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease[J]. Nature Communications, 2017, 8: 15384. DOI: 10.1038/ncomms15384.
 
 
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