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Cellular and molecular dysregulation of the esophageal epithelium in systemic sclerosis

ABSTRACT: Individuals with systemic sclerosis (SSc) often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. However, the pathogenesis of esophageal dysmotility in SSc is poorly understood. To determine whether distinct changes in esophageal epithelial cells contribute to impaired motility in SSc, we investigated the stratified squamous esophageal epithelium from proximal and distal biopsies using single-cell RNA sequencing (n=306,372 cells) in individuals with SSc compared those with gastroesophageal reflux disease (GERD) as well as healthy controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295274 | GEO | 2025/10/10

REPOSITORIES: GEO

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Project description:Background: Gastroesophageal reflux disease (GERD) is a chronic condition linked to inflammatory and cancerous alterations in esophageal epithelium. Despite the widespread use of acid suppressing proton pump inhibitors (PPIs), the incidence of esophageal adenocarcinoma (EAC) keeps increasing, underscoring the possible importance of nonacidic reflux components like pepsin in cancer development. Pepsin, a therapeutic target for GERD, has been associated with epithelial damage and metaplasia. Methods: The goal of this study was to investigate the effect of pepsin, at a transcriptional level, and to assess the potential therapeutic value of amprenavir, as a pepsin inhibitor, in vitro. Human esophageal cell lines, immortalized from normal (Het-1A) and Barrett’s esophagus (BAR-T), were exposed to pH 7.0 buffer containing pepsin and/or amprenavir for 1 hour (n=3). RNA-seq was conducted to detect differentially expressed genes (DEGs) with FDR ≤ 0.05 and |log2 fold change| ≥ 0.375, and Ingenuity Pathway Analysis (IPA) was performed to identify the top significantly biological pathways. Results: Pepsin exposure caused notable transcriptomic alterations in both Het-1A and BAR-T cells, specifically impacting mitochondrial function, oxidative phosphorylation, and pathways associated with epithelial integrity, cell signaling, and inflammatory responses. Amprenavir alleviated several of these effects, indicating a protective function in epithelial impairment resulting from peptic injury. Of interest, Het-1A and BAR-T cells demonstrated different reactions to pepsin treatment; BAR-T cells revealed more pronounced changes in pathways associated with wound healing, chronic epithelial formation, and repair, whereas Het-1A cells showed more substantial alterations in systemic damage and mitochondrial pathways. Conclusion: The results of this study underscore the detrimental impact of pepsin on esophageal epithelial cells despite PPI therapy and highlight amprenavir as a promising therapeutic option to mitigate pepsin-induced epithelial injury. Further research to validate these in vitro findings is warranted to assess the efficacy of amprenavir for GERD-related damage and carcinogenesis.

Project description:Background & Aims: Because the pathophysiology of GERD is not fully understood, presently used drug target only one or more of the known underlying mechanisms but are not fully effective in all patients. 1Identifying novel central targets may pave the way to develop more effective agents. Methods: A surgical model of sub-chronic reflux esophagitis was developed. Wistar rats were pretreated for 7days with omeprazole (standard proton pump inhibitor) or STW5 (herbal preparation of established efficacy in gastro-intestinal disorders). Treatment was continued for 10days after surgery, rats were sacrificed and esophagi excised. Histological, proteomic and transcriptomic methods were applied to identify reflux induced changes and treatment responses. Results: Protection against reflux induced inflammation was achieved by both test drugs. Both reduced macroscopic and microscopic lesions of the esophagi as well as most measured pro-inflammatory cytokines without significantly affecting NF-kB activity. Proteomic and transcriptomic analysis identified CINC1-3, MIP-1/3Î±, MIG, RANTES and IL-1Î² as highly relevant mediators in GERD. Other highly regulated genes were those of IL-6, CCL3, CCL7 and LOX-1. Many affected cyto-/chemokines were involved in the TREM-1 signaling pathway. The fatty acid receptor GPR84 was highly up-regulated in esophagitis but down-regulated by both drugs. This was confirmed by Western blot and immune-histochemical staining, showing for the first time expression of this receptor in esophageal tissue and its possible involvement in GERD. Conclusion: STW5 and omeprazole target a broad spectrum of molecules involved in immunological and inflammatory processes, of which IL-8 (CINC1-3), TREM-1 pathway and GPR84 are proposed to be most promising novel targets for the treatment of GERD. Refluxesophagitis was surgically induced. Wistar rats were pretreated for 7 days with omeprazole or STW5. Treatment was continued for 10days after surgery, rats were sacrificed and esophagi exiced. The study had 5 groups. Group 1: sham operated, Group 2: esophagitis group, untreated, Group3: esophagitis treated with STW5 0.5ml/kg. Group 4: esophagitis treated with STW5 2ml/kg. Group 5: esophagitis treated with Omeprazole (30mg/kg). 4 microarrays from esophageal tissue and blood from 4 animals of each group were performed.

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Cellular and molecular dysregulation of the esophageal epithelium in systemic sclerosis

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