Gut Liver.  2023 Nov;17(6):905-915. 10.5009/gnl220308.

Downregulation of Heat Shock Protein 72 Contributes to Fibrostenosis in Crohn’s Disease

• Kim SW
• Lee JY
• Lee HC
• Ahn JB
• Kim JH
• Park IS
• Cheon JH
• Kim DH

• KMID: 2548449
• DOI: http://doi.org/10.5009/gnl220308

Abstract

Background/Aims
Crohn’s disease (CD) with recurrent inflammation can cause intestinal fibrostenosis due to dysregulated deposition of extracellular matrix. However, little is known about the pathogenesis of fibrostenosis. Here, we performed a differential proteomic analysis between normal, inflamed, and fibrostenotic specimens of patients with CD and investigated the roles of the candidate proteins in myofibroblast activation and fibrosis.
Methods
We performed two-dimensional difference gel electrophoresis and identified candidate proteins using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and orbitrap liquid chromatography-mass spectrometry. We also verified the levels of candidate proteins in clinical specimens and examined their effects on 18Co myofibroblasts and Caco-2 intestinal epithelial cells.
Results
We identified five of 30 proteins (HSP72, HSPA5, KRT8, PEPCK-M, and FABP6) differentially expressed in fibrostenotic CD. Among these proteins, the knockdown of heat shock protein 72 (HSP72) promoted the activation and wound healing of myofibroblasts. Moreover, knockdown of HSP72 induced the epithelial-mesenchymal transition of intestinal epithelial cells by reducing E-cadherin and inducing fibronectin and α-smooth muscle actin, which contribute to fibrosis.
Conclusions
HSP72 is an important mediator that regulates myofibroblasts and epithelial-mesenchymal transition in fibrosis of CD, suggesting that HSP72 can serve as a target for antifibrotic therapy.

Keyword

Crohn disease; Epithelial-mesenchymal transition; Fibrostenosis; Myofibroblast; Heat-shock proteins