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Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy.

ABSTRACT: Intestinal epithelia impairment of inflammatory bowel disease (IBD) leads to the leakage of bacteria and antigens and the consequent persistent immune imbalance. Restoring the epithelial barrier is a promising therapeutic target but lacks effective and safe clinical interventions. By identifying the catalase (CAT) presence in the IBD pathological environment, we herein develop a CAT-catalyzed pathologically coating on the damaged epithelial barrier to inhibit intestinal leakage for IBD therapy. With the codelivery of CaO₂ (a CAT substrate) and dopamine, the nanosystem can enable CAT-catalyzed oxygen (O₂) production and in-situ polymerization of dopamine and then yield a thin and integrative polydopamine (PDA) coating on the intestinal barrier due to the highly adhesive property of PDA. In vivo study demonstrates that PDA coating provides not only a protective barrier by restricting intestinal leakage but also a favorable anti-inflammation effect. Beyond drug management, this work provides a physical repair strategy via catalyzed coating for IBD therapy.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC10668504 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy.

Zhao Yuge Y He Ruiqing R Zang Jie J Yin Weimin W Su Runping R Xiong Wei W Xu Weihua W Zhang Jiaxin J Liu Yiqiong Y Ren Tianbin T Huang Yongzhuo Y Li Yongyong Y

Journal of nanobiotechnology 20231124 1

Intestinal epithelia impairment of inflammatory bowel disease (IBD) leads to the leakage of bacteria and antigens and the consequent persistent immune imbalance. Restoring the epithelial barrier is a promising therapeutic target but lacks effective and safe clinical interventions. By identifying the catalase (CAT) presence in the IBD pathological environment, we herein develop a CAT-catalyzed pathologically coating on the damaged epithelial barrier to inhibit intestinal leakage for IBD therapy. ...[more]

PMID: 37996883

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Project description:BackgroundLoss of intestinal epithelial barrier integrity is a critical component of Inflammatory Bowel Disease (IBD) pathogenesis. Co-expression regulation of ligand-receptor pairs in IBD mucosa has not been systematically studied. Targeting ligand-receptor pairs which are induced in IBD mucosa and function in intestinal epithelial barrier integrity may provide novel therapeutics for IBD.MethodsWe performed transcriptomic meta-analysis on public IBD datasets combined with cell surface protein-protein-interaction (PPI) databases. We explored primary human/mouse intestinal organoids and Caco-2 cells for expression and function studies of uPA-uPAR (prime hits from the meta-analysis). Epithelial barrier integrity was measured by Trans-Epithelial Electrical Resistance (TEER), FITC-Dextran permeability and tight junction assessment. Genetic (CRISPR, siRNA and KO mice) and pharmacological (small molecules, neutralizing antibody and peptide inhibitors) approaches were applied. Mice deficient of uPAR were studied using the Dextran Sulfate Sodium (DSS)-induced colitis model.FindingsThe IBD ligand-receptor meta-analysis led to the discovery of a coordinated upregulation of uPA and uPAR in IBD mucosa. Both genes were significantly upregulated during epithelial barrier breakdown in primary intestinal organoids and decreased during barrier formation. Genetic inhibition of uPAR or uPA, or pharmacologically blocking uPA-uPAR interaction protects against cytokine-induced barrier breakdown. Deficiency of uPAR in epithelial cells leads to enhanced EGF/EGFR signalling, a known regulator of epithelial homeostasis and repair. Mice deficient of uPAR display improved intestinal barrier function in vitro and during DSS-induced colitis in vivo.InterpretationOur findings suggest that blocking uPA-uPAR interaction via pharmacological agents protects the epithelial barrier from inflammation-induced damage, indicating a potential therapeutic target for IBD.FundingThe study was funded by Boehringer Ingelheim.

Dataset Information

Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy.

Publications

Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy.

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