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.

组织纤维化和平滑肌增生引起的狭窄形成是严重克罗恩的标志 疾病（CD）。尽管狭窄形成与慢性感染有关，但无抗炎 除了手术方法外，治疗对此是有效的。但是，手术后返回前静脉前的回报 地区几乎是100％。研究炎症无关机制在纤维化中的可能作用 需要增生。机械应力（MS）与组织变形，水肿，纤维化和 CD中通常会遇到扩张。我们假设MS在纤维化和 CD中的增生。我们在定义明确的CD啮齿动物模型中发现TNBS内注射诱导A 局部透壁炎症随着远端结肠的管腔变窄，并在 段近端炎症。我们发现结缔组织生长因子（CTGF）的表达和 结肠平滑肌细胞（SMC）中脑衍生的神经营养因子（BDNF）不仅诱导 在炎症部位，但在炎症的片段代理中。我们还检测到了重要的 注射部位中的纤维化和增生和增生，段是21天的注射段。这 炎症远端的非段落段未显示CTGF和BDNF的增加，或者纤维化和 增生，表明MS依赖性机制。此外，如果防止机械距离 仅用液体饮食喂养大鼠，这些饮食模仿CD管理中的独家肠内营养（EEN）， CTGF和BDNF的表达大大减弱，纤维化显着改善。 机械拉伸体外诱导CTGF和BDNF在结肠SMC中的表达，并激活转录 激活剂是与YES相关的蛋白-1（YAP）。此外，发现纤维雌激素中的YAP活性显着增加 人类的CD组织。我们提出，CD中的透壁感染会导致感染部位的MS，并 膨胀的段代理炎症，MS诱导YAP依赖性机械敏感性 CTGF和BDNF的表达有助于纤维化和增生。研究的具体目的 为：1。确定MS是否在CD中的肠纤维化和SMC增生中起作用。我们会区分 通过评估纤维化，SMC生长和表达的位点特异性变化，从炎症发出MS的影响 注射部位（注射和MS）的CTGF和BDNF，近端（与 在CD模型中，MS）和远端（既没有炎症也没有MS）。 MS在 ECM生产和SMC增生将在没有MS的CD中进一步评估（供大鼠供应液体饮食）和 在仅MS（机械异议）的模型中。 2。研究MS诱导的信号传导机制 CTGF和BDNF的YAP激活和YAP依赖性表达。 3。检查 YAP介导的CTGF和BDNF在纤维化和增生中的机械敏感表达。可能 纤维化和增生中的炎症与MS之间的合作也将进行研究。

项目成果

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

• DOI: 10.3390/nu15102275
• 发表时间: 2023-05-11
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Recharla N;Geesala R;Shi XZ
• 通讯作者: Shi XZ

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。

• DOI: 10.1093/ibd/izad158
• 发表时间: 2024
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Geesala,Ramasatyaveni;Zhang,Ke;Lin,You-Min;Johnson,JohnC;Cong,Yingzi;Cohn,Steven;Shi,Xuan-Zheng
• 通讯作者: Shi,Xuan-Zheng