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.

由组织纤维化和平滑肌增生引起的狭窄形成是严重克罗恩病的标志

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酯及其在炎​​症性肠病中的治疗作用：文献综述。

• 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