MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Céline Mamie, Ramona S Bruckner, Silvia Lang, Nahum Y Shpigel, Matthias Turina, Andreas Rickenbacher, Daniela Cabalzar-Wondberg, Yolanda Chvatchko, Gerhard Rogler, Michael Scharl
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引用次数: 1

Abstract

Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.

Abstract Image

Abstract Image

MMP9在瘘管性CD患者肠瘘及人异种移植小鼠模型肠瘘中的表达。
在克罗恩病(CD)的治疗中,瘘管治疗是一个主要的未满足的医疗需求。目前的医学治疗,如抗肿瘤坏死因子抗体治疗,往往是不够的,不能实现永久瘘管闭合。先前发表的数据指出金属蛋白酶-9 (MMP-9)/明胶酶B在瘘发病机制中的关键作用。该项目的目的是详细研究MMP-9在不同类型瘘管中的表达,并证实MMP-9是CD患者瘘管治疗的潜在靶点。对来自肛周瘘、肠肠瘘和抗肿瘤坏死因子治疗无效患者的瘘管标本进行总MMP-9和活性MMP-9、细胞角蛋白8 (CK-8)的免疫组化和活性MMP-9/CK-8的共染色。此外,对异种移植小鼠模型(抗tnf治疗或未治疗)的瘘管进行分析。总MMP-9蛋白和活性MMP-9蛋白在肛周瘘管和肠肠瘘管内壁细胞中检测到。值得注意的是,总MMP-9和活性MMP-9也在对抗tnf治疗无反应的CD患者的瘘管中表达。有趣的是,我们检测到相当多的活性MMP-9和CK-8共染色,特别是在瘘道内衬细胞和瘘周围的移行细胞中。此外,在抗tnf治疗和未治疗的异种移植物瘘中均可检测到总MMP-9和活性MMP-9。综上所述,我们的数据表明,MMP-9参与了CD患者、不同来源的瘘管的发病机制,特别是对抗tnf治疗无反应的患者。我们的异种移植瘘管模型适用于体内研究MMP-9靶向作为瘘管治疗的可能治疗作用。
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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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