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

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $355,500

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10147880
- **Project number:** 5R01DK124611-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Xuan-Zheng Peter Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,500
- **Award type:** 5
- **Project period:** 2020-04-21 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147880

## Citation

> US National Institutes of Health, RePORTER application 10147880, Pathogenic Role of Mechanical Stress in Fibrosis and Tissue Remodeling in Crohn's Disease (5R01DK124611-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10147880. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*