Pathogenic Role of Mechanical Stress in Fibrosis and Tissue Remodeling in Crohn's Disease

机械应力在克罗恩病纤维化和组织重塑中的致病作用

• 批准号: 10549370
• 负责人: Xuan-Zheng Peter Shi
• 金额: $ 35.55万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549370
• 关键词: Abbreviations; Affect; American; Animal Feed; Anti-Inflammatory Agents; Attenuated; Brain-Derived Neurotrophic Factor; Caring; Chronic; Collagen; Colon; Complication; Crohn' s disease; Deposition; Development; Diet; Disease Management; Disease model; Distal; Edema; Enteral Nutrition; Excision; Extracellular Matrix; Fibrosis; Gastrointestinal tract structure; Gene Expression; Haptens; Histologic; Human; Hyperplasia; Hypertrophy; In Vitro; Inflammation; Inflammatory Bowel Diseases; Injections; Intervention Studies; Intestinal Fibrosis; Intestines; Intracolonic; Length; Liquid substance; Mechanical Stress; Mechanics; Mediating; Medical; Mesenchymal; Modeling; Muscle; Names; Obstruction; Operative Surgical Procedures; Pathogenicity; Pathologic; Pathway interactions; Patients; Play; Process; Production; Proteins; Protocols documentation; Rattus; Reagent; Recurrence; Reporting; Research; Rodent; Rodent Model; Role; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Specimen; Stretching; Time; Tissues; Transcription Coactivator; Trinitrobenzenesulfonic Acid; Ulcerative Colitis; Up-Regulation; Virulence Factors; cell growth; cell type; connective tissue growth factor; cost; effective therapy; feeding; gut inflammation; improved; mRNA Expression; new therapeutic target; preclinical study; prevent; protein expression; screening

Stricture formation due to tissue fibrosis and smooth muscle hyperplasia is a hallmark of severe Crohn’s disease (CD). Although stricture formation is associated with chronic inflammation, no anti-inflammatory treatment is effective for it, except surgical approaches. However, post-surgery recurrences in the pre-stenotic region are almost 100%. Studies into the possible role of inflammation-independent mechanisms in fibrosis and hyperplasia are needed. Mechanical stress (MS) associated with tissue deformation, edema, fibrosis, and distention are commonly encountered in CD. We hypothesize that MS plays a critical role in fibrosis and hyperplasia in CD. We found in a well-defined rodent model of CD that intracolonic injection of TNBS induced a localized transmural inflammation with lumen narrowing in the distal colon and marked distention in the segment proximal to inflammation. We found that expression of connective tissue growth factor (CTGF) and brain-derived neurotrophic factor (BDNF) in colon smooth muscle cells (SMC) was markedly induced not only in the inflammation site but in the distended segment proximal to inflammation. We also detected significant fibrosis and hyperplasia in the inflammation site and the segment proximal to inflammation by 21 days. The non-distended segment distal to inflammation did not show any increased CTGF and BDNF, or fibrosis and hyperplasia, indicating a MS dependent mechanism. Furthermore, if mechanical distention was prevented by feeding rats with only liquid diet, which mimics exclusive enteral nutrition (EEN) in CD management, expression of CTGF and BDNF was dramatically attenuated and fibrosis was significantly improved. Mechanical stretch in vitro induced expression of CTGF and BDNF in colon SMC, and activated transcription activator yes-associated protein-1 (YAP). Moreover, YAP activity is found markedly increased in fibrostenotic CD tissues in humans. We propose that transmural inflammation in CD causes MS in the inflammation site and the distended segment proximal to inflammation, and the MS induces YAP-dependent mechanosensitive expression of CTGF and BDNF, which contribute to fibrosis and hyperplasia. The specific aims of the study are: 1. To determine if MS plays a role in intestinal fibrosis and SMC hyperplasia in CD. We will differentiate the effect of MS from inflammation by assessing site-specific changes of fibrosis, SMC growth, and expression of CTGF and BDNF in the site of inflammation (with both inflammation and MS), the segments proximal (with MS) and distal (with neither inflammation nor MS) to the inflammation site in the CD model. The role of MS in ECM production and SMC hyperplasia will be further assessed in CD without MS (rats fed with liquid diet) and in a model with MS only (mechanical obstruction). 2. To investigate the signaling mechanisms of MS-induced YAP activation and YAP-dependent expression of CTGF and BDNF. 3. To examine the pathogenic roles of YAP mediated mechanosensitive expression of CTGF and BDNF in fibrosis and hyperplasia. The possible cooperation between inflammation and MS in fibrosis and hyperplasia will be investigated as well.

由于组织纤维化和平滑肌增生而形成的狭窄是严重克罗恩病的标志 尽管狭窄的形成与慢性炎症有关，但没有抗炎作用。 除手术治疗外，治疗方法均有效，但术后狭窄易复发。 区域几乎 100% 研究了炎症独立机制在纤维化中的可能作用。 以及与组织变形、水肿、纤维化和相关的机械应力（MS）。 膨胀是 CD 中常见的情况，我们勇敢地承认 MS 在纤维化和纤维化中起着关键作用。 我们在明确的 CD 啮齿动物模型中发现，结肠内注射 TNBS 会诱导 CD 增生。 局部透壁炎症，远端结肠管腔变窄，结肠明显扩张 我们发现结缔组织生长因子（CTGF）和近端节段的表达。 结肠平滑肌细胞（SMC）中的脑源性神经营养因子（BDNF）不仅被显着诱导 在炎症部位，但在靠近炎症的远端部分，我们也检测到了显着的变化。 21天时，炎症部位和邻近炎症的节段出现纤维化和增生。 炎症远端非扩张段未显示任何 CTGF 和 BDNF 增加，或纤维化和 增生，表明 MS 依赖性机制。此外，如果通过以下方式防止机械扩张。 仅用流质饮食喂养大鼠，这模仿 CD 管理中的纯肠内营养 (EEN)， CTGF和BDNF的表达显着减弱，纤维化显着改善。 体外机械拉伸诱导结肠 SMC 中 CTGF 和 BDNF 的表达，并激活转录 此外，YAP 活性在纤维狭窄中显着增加。 我们认为 CD 中的跨壁炎症会导致炎症部位的多发性硬化症 (MS)。 MS 诱导 YAP 依赖性机械敏感 CTGF 和 BDNF 的表达，有助于纤维化和增生 该研究的具体目的。 是： 1. 确定 MS 是否在 CD 中的肠纤维化和 SMC 增生中起作用。 通过评估纤维化、SMC 生长和表达的位点特异性变化来评估炎症对 MS 的影响 CTGF 和 BDNF 在炎症部位（有炎症和 MS）、近端节段（有 MS）和 CD 模型中炎症部位的远端（既无炎症也无 MS）MS 在其中的作用。 ECM 产生和 SMC 增生将在没有 MS 的 CD 中进一步评估（用流质饮食喂养的大鼠）和 在仅具有 MS 的模型中（机械阻塞） 2. 研究 MS 诱导的信号传导机制。 YAP 激活以及 CTGF 和 BDNF 的 YAP 依赖性表达 3. 检查致病作用。 YAP 介导纤维化和增生中 CTGF 和 BDNF 的机械敏感性表达。 炎症与多发性硬化症在纤维化和增生方面的合作也将得到研究。

项目成果

Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review.

肠道微生物代谢物丁酸盐及其在炎症性肠病中的治疗作用：文献综述。

• 发表时间: 2023-05-11
• 影响因子: 5.9
• 作者: Recharla, Neeraja;Geesala, Ramasatyaveni;Shi, Xuan
• 通讯作者: Shi, Xuan

A TNBS-Induced Rodent Model to Study the Pathogenic Role of Mechanical Stress in Crohn's Disease.

TNBS 诱导的啮齿动物模型，用于研究机械应力在克罗恩病中的致病作用。

• 发表时间: 2022-03-01
• 作者: Geesala, Ramasatyaveni;Lin, You;Zhang, Ke;Qiu, Suimin;Shi, Xuan
• 通讯作者: Shi, Xuan

Exclusive Enteral Nutrition Alleviates Th17-Mediated Inflammation via Eliminating Mechanical Stress-Induced Th17-Polarizing Cytokines in Crohn's-like Colitis.

独家肠内营养通过消除克罗恩病样结肠炎中机械应力诱导的 Th17 极化细胞因子来减轻 Th17 介导的炎症。

• 发表时间: 2024-03-01
• 影响因子: 4.9
• 作者: Geesala, Ramasatyaveni;Zhang, Ke;Lin, You;Johnson, John C;Cong, Yingzi;Cohn, Steven;Shi, Xuan
• 通讯作者: Shi, Xuan

Exclusive Enteral Nutrition Beneficially Modulates Gut Microbiome in a Preclinical Model of Crohn's-like Colitis.

独家肠内营养有益地调节克罗恩病样结肠炎临床前模型中的肠道微生物组。

• 发表时间: 2024-01-26
• 影响因子: 5.9
• 作者: Geesala, Ramasatyaveni;Recharla, Neeraja;Zhang, Ke;Johnson, John C;Golovko, George;Khanipov, Kamil;Brining, Douglas L;Shi, Xuan
• 通讯作者: Shi, Xuan