Use of a dpp-4 inhibitor for the preparation of a medicament for the prevention and / or treatment of a stricture of the digestive tract

Abstract

The application provides application of a DPP-4 inhibitor in preparation of a medicine for preventing and / or treating digestive tract stenosis, and belongs to the technical field of medicines. Based on morphological performance of stenosis segment esophageal tissue outer membrane scar fibrosis, it is found that a DPP-4+ fibroblast subpopulation in stenosis segment esophageal outer membrane fibrosis hyperplasia tissue is obviously highly expressed. The DPP-4 inhibitor can prevent and treat refractory stenosis after esophageal ESD operation through anti-inflammatory and anti-fibrosis effects on stenosis segment esophageal outer layer tissue, and is a powerful supplement to the current esophageal ESD postoperative stenosis which focuses on intraluminal prevention and treatment of esophageal submucosa and part of inherent muscle layer scar fibrosis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to the application of DPP-4 inhibitors in the preparation of drugs for the prevention and / or treatment of gastrointestinal strictures. Background Technology

[0002] Endoscopic submucosal dissection (ESD) primarily removes the esophageal mucosa and part of the submucosa. Most esophageal fibroblasts and fibroblastic components are located within the connective tissue, mainly in the submucosa and adventitia. After ESD, fibroblasts around the wound are activated, primarily from submucosal fibroblasts and some muscle layer fibroblasts induced by injury to become myofibroblasts and inflammatory fibroblasts, participating in esophageal fibrosis and scar hyperplasia. During esophageal repair after ESD, starting one week post-surgery, homeostatic fibroblasts gradually transform into extracellular matrix, inducing myofibroblasts and inflammatory fibroblasts. Myofibroblast contraction leads to esophageal lumen narrowing, while inflammatory fibroblasts can induce collagen deposition, resulting in scar formation and ultimately esophageal stricture.

[0003] Research on refractory benign esophageal strictures, whether using balloon dilation, radial incision, skeletal dilation, or local and systemic drug application, botulinum toxin injection, epithelial tissue transplantation, or stem cell therapy, has all focused on endoscopic treatment within the esophageal lumen, aiming to prevent restenosis by altering the path of fibrous scar hyperplasia, primarily in the submucosa, through physical or biochemical methods. However, the role of the outer layers of tissue beyond the muscularis propria, especially the fibroblast subsets of the adventitia, in the progression of stricture has not received due attention.

[0004] The process of esophageal stricture after ESD generally includes the following main stages: severe inflammatory response, scar fibrosis and contracture, and collagen deposition. To date, there are still no detailed reports on the molecular mechanisms of action in the process of esophageal fibrosis after ESD.

[0005] Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used hypoglycemic drugs in clinical practice. They have a high safety profile for long-term use and are easy to administer. Currently, there are no reports of DPP-4 inhibitors inhibiting gastrointestinal strictures. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide the use of DPP-4 inhibitors in the preparation of medicaments for the prevention and / or treatment of gastrointestinal strictures.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] Application of DPP-4 inhibitors in the preparation of drugs for the prevention and / or treatment of gastrointestinal strictures.

[0009] Preferably, the DPP-4 inhibitors include sitagliptin, linagliptin, saxagliptin, vildagliptin, and alogliptin.

[0010] Preferably, the gastrointestinal stricture includes stricture following esophageal ESD.

[0011] Preferably, the DPP-4 inhibitor inhibits the fibrotic proliferation of the epithelial scar after ESD.

[0012] Preferably, the DPP-4 inhibitor inhibits DPP-4 expression in the outer membrane layer.

[0013] Preferably, the DPP-4 inhibitor reduces the proportion of DPP-4+ fibroblast subsets.

[0014] Preferably, the DPP-4 inhibitor reduces inflammatory response, reduces cell apoptosis, and reduces the expression of IFN-α and IL-6.

[0015] Preferably, the DPP-4 inhibitor promotes the expression of myofibroblast marker molecules and reduces the expression of TBX21 transcription factor.

[0016] Preferably, the DPP-4 inhibitor reduces cell-cell interactions in the FGF signaling pathway.

[0017] Preferably, the drug includes pharmaceutically acceptable excipients.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] This invention provides the application of DPP-4 inhibitors in the preparation of drugs for the prevention and / or treatment of gastrointestinal strictures. Based on the morphological manifestations of fibrotic scarring in the esophageal adventitia of the stricture segment, this invention reveals a significantly high expression of DPP-4+ fibroblast subsets in the fibrotic proliferative tissue of the esophageal adventitia of the stricture segment. DPP-4 inhibitors can prevent and treat refractory strictures after esophageal ESD surgery through their anti-inflammatory and anti-fibrotic effects targeting the outer layer of the esophageal stricture segment. This provides a powerful supplement to current methods for preventing fibrotic scarring in the submucosa and part of the muscularis propria after esophageal ESD surgery. Attached Figure Description

[0020] Figure 1 A schematic diagram illustrating the molecular mechanism by which DPP-4 inhibitors prevent and treat esophageal stricture after ESD.

[0021] Figure 2This is a schematic diagram of endoscopic modeling of stenosis after ESD; where a) is a schematic diagram of successful stenosis modeling, with the stenosis resembling a needle tip; b) shows balloon dilation to 15mm if the stenosis diameter is less than 5mm; c) is a schematic diagram of the entire esophagus at 22 weeks; d) shows the stenotic segment, transition segment, and normal segment of the circumferential specimen.

[0022] Figure 3 This is a schematic diagram of endoscopic modeling in the ESD experimental group that received oral linagliptin (a DPP-4 inhibitor) 10 mg / d 2 weeks in advance; where a is a schematic diagram of esophageal stricture in the control group; b is a schematic diagram of esophageal stricture after oral linagliptin, showing significant relief of esophageal stricture; c is a schematic diagram of the entire esophagus at 22 weeks; d is circumferential specimen showing the stricture segment, transition segment, and normal segment of esophageal tissue.

[0023] Figure 4 Single-cell sequencing analysis was used to analyze cell population changes (blank control group vs. ESD postoperative stenosis group); where a is the esophageal tissue cell population in the ESD postoperative stenosis group (orange population represents fibroblasts); b is the proportion of fibroblasts in the blank control and ESD postoperative stenosis groups; c is the expression of fibroblast markers.

[0024] Figure 5 To analyze the proportions of proliferating fibroblast subsets in the blank control group and the ESD postoperative stricture group using single-cell sequencing; where a represents the fibroblast populations in the esophageal tissue of the ESD postoperative stricture group (circled is the DPP-4+ subset); b represents the proportion of DPP-4+ subset cells in fibroblasts; and c represents the DPP-4+ gene expression level in the ESD postoperative stricture group.

[0025] Figure 6 The differential expression of genes and cytokines in fibroblasts was analyzed by single-cell sequencing in the blank control group and the ESD postoperative stenosis group; where a is a scatter plot of data analysis and b is a statistical ensemble plot.

[0026] Figure 7 Hallmark and KEGG analyses were performed on fibroblasts that formed stenosis after ESD surgery, comparing the results of the blank control group with those of the control group. In the figure, a represents the KEGG analysis results, and b represents the Hallmark analysis results.

[0027] Figure 8 This study compares the transcription factor characteristics of the blank control group versus the ESD postoperative stenosis group. Among them, a) is the transcript of the DPP-4+ subset in the transcriptional network analysis; b) is the signaling pathway with statistical differences; c) is the "Peak" formed by TBX21 near the DPP-4 promoter and transcription start site.

[0028] Figure 9This section analyzes the downstream effects of the DPP-4+ subset; where a) shows the close connections between fibroblasts and T cells, macrophages, nerves, and endothelial cells; b) shows a schematic diagram of the connections between DPP-4+ subset fibroblasts and cells such as fine T cells and macrophages; c) shows a schematic diagram of the number of pathways connecting fibroblasts with other cells; d) shows the association strength of multi-ligand pathways in each fibroblast subset; and e) shows a schematic diagram of FGF expression intensity in each fibroblast subset.

[0029] Figure 10 The interaction between DPP-4+ fibroblast subsets and other cell receptor-ligands;

[0030] Figure 11 The images show endoscopic animal experiments and immunohistochemical staining results; A shows the degree of stenosis and the number of dilations required throughout the entire process in the ESD postoperative stenosis group and the ESD experimental group treated with linagliptin; B shows the scar fibrosis and hyperplasia in different groups.

[0031] Figure 12 The results of immunofluorescence analysis are shown for the postoperative stenosis group, blank control group, and ESD experimental group treated with linagliptin; where A represents the expression of scar ring proliferation outside the muscle layer and B represents the expression of scar ring proliferation inside the cavity.

[0032] Figure 13 The changes in cell subsets were compared between the blank control group, the ESD postoperative stenosis group, and the ESD experimental group treated with linagliptin. Specifically, a) showed the percentage of fibroblasts in the linagliptin group (DPP4) relative to the normal group (D) and the stenosis group (Cstr); b) showed the percentage of characteristic cell types after linagliptin treatment; c) showed the changes in DPP-4+ fibroblast subsets (marked with dashed lines); and d) showed DPP-4 expression in different groups.

[0033] Figure 14 The HALLMARK and KEGG functional enrichment analysis was performed to analyze the changes in fibroblast signaling pathways after the application of DPP-4 inhibitors. The top figure shows the functionally enriched molecules of HALLMARK; the middle figure shows the changes in fibroblast signaling pathways after the application of DPP-4 inhibitors after the application of KEGG functional enrichment analysis; and the bottom figure shows the signaling pathways with statistical differences found based on the above functional analysis.

[0034] Figure 15 The differences in gene and cytokine expression in fibroblasts were analyzed by single-cell sequencing of the blank control group, the ESD postoperative stenosis group, and the ESD experimental group treated with linagliptin. The left figure is a scatter plot of data analysis, and the right figure is a statistical ensemble plot.

[0035] Figure 16The study compared the blank control group with the ESD postoperative stenosis group and the ESD experimental group treated with linagliptin. Single-cell sequencing analysis was used to analyze the changes in downstream cellular pathways of fibroblasts. The left figure shows the changes in each cell subpopulation; the middle figure shows the changes in signaling pathways; and the right figure shows that the fibroblasts affect downstream cells through the FGF signaling pathway, as found by integrated analysis. Detailed Implementation

[0036] This invention provides the use of DPP-4 inhibitors in the preparation of medicaments for the prevention and / or treatment of gastrointestinal strictures, said DPP-4 inhibitors including sitagliptin, linagliptin, saxagliptin, vildagliptin, and alogliptin.

[0037] In this invention, the digestive tract stricture includes stricture following esophageal ESD (esophageal endoscopic submucosal dissection). ESD is the preferred treatment for early esophageal cancer, and postoperative stricture is a common complication. Large-area esophageal ESD procedures are prone to refractory strictures, requiring repeated endoscopic dilation; existing treatments have high restenosis rates and uncontrollable side effects. This invention has found that the stricture segment of the esophagus contains an intraluminal scar ring primarily composed of the submucosa and an extraluminal scar ring primarily composed of the esophageal adventitia. Current treatments primarily focus on endoscopic intervention targeting the intraluminal scar ring, while the extraluminal scar ring has been neglected. This invention also found that the trauma of large-area esophageal ESD surgery leads to changes in the inflammatory immune microenvironment within the entire esophageal tissue, resulting in high expression of factors such as CD276, TGFB1, TNFSF-9, CXCL10, IFN-α, and IL-6. The inflammatory microenvironment upregulates the TBX21 transcript, which, as a DPP-4 promoter, binds to the nuclei of COL15A1+ homeostatic fibroblasts in the esophageal adventitia, thereby inducing them to transform from homeostatic fibroblasts into DPP-4+ subsets. These subsets then influence downstream immune cells through three major pathways: FGF, NOTCH, and KIT. Among these, the FGF pathway has the most significant impact on macrophages. DPP-4+ fibroblasts and macrophages can form receptor-ligand interactions such as COL1A1-CD44 and COL1A family-ITGA1, which may further affect downstream collagen deposition and aggravate scar fibrosis in the adventitia of the stenotic segment of the esophagus. Macroscopically, this manifests as the current clinical situation where refractory esophageal strictures do not respond well to endoscopic treatment. This invention has found that DPP-4 inhibitors can effectively prevent and treat esophageal strictures after ESD (esophageal percutaneous stenosis), and a schematic diagram of its molecular mechanism is shown below. Figure 1 As shown.

[0038] In this invention, the DPP-4 inhibitor inhibits the fibrotic proliferation of the outer membrane scar after ESD.

[0039] In this invention, the DPP-4 inhibitor inhibits the expression of DPP-4 in the outer membrane layer, and the DPP-4 inhibitor can also inhibit the expression of IL-33 in the luminal stenosis ring.

[0040] In this invention, the DPP-4 inhibitor reduces the proportion of DPP-4+ fibroblast subsets.

[0041] In this invention, the DPP-4 inhibitor reduces inflammatory response, reduces cell apoptosis, and reduces the expression of IFN-α and IL-6. The DPP-4 inhibitor modulates the immune microenvironment through its anti-inflammatory effect.

[0042] In this invention, the DPP-4 inhibitor promotes the expression of myofibroblast marker molecules and reduces the expression of TBX21 transcription factor. TBX21 transcription factor can upregulate DPP-4 expression, and the DPP-4 inhibitor inhibits the expression of TBX21 transcription factor, which can make the immune microenvironment more stable.

[0043] In this invention, the DPP-4 inhibitor reduces the interaction between DPP-4+ fibroblast subsets and macrophages in the FGF signaling pathway, thereby inhibiting the occurrence of stenosis.

[0044] In this invention, the drug comprises pharmaceutically acceptable excipients, and different dosage forms are prepared by adding excipients. These dosage forms include powders, decoctions, pills, capsules, tablets, granules, and oral liquids. This invention does not specifically limit the source of the DPP-4 inhibitor; any commercially available product conventional in the art can be used.

[0045] In this invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0046] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0047] Example 1

[0048] 1. Constructing an animal model

[0049] 1.1 Experimental pigs (weight: 35.2-45.4 kg) were obtained from Shanghai Chedun Experimental Animal Breeding Farm Co., Ltd. Preliminary experiments were conducted using esophageal ESD modeling: (1) The anal and oral sides of the lesion area were marked; (2) A submucosal injection (10 mL of physiological saline) was performed on the anal side, and a circumferential incision was made along the anal side marking from the mucosa to the submucosal area; similarly, a submucosal injection (10 mL of physiological saline) was performed on the oral side; (3) Intermittent incisions were made on the oral side to form tunnel openings, and multiple tunnels were established to the anal side circumferential incision, with the tunnel intervals cut; (4) The oral side tunnels were removed. (5) Before establishing the tunnel, make a circumferential incision in the submucosal layer on the anal side as the end point of the tunnel; (6) Use a Dual knife or IT knife to operate; (7) After forming the tunnel in the middle, use an insulated electrocautery knife to expand the tunnel to the left and right sides; (8) Peel off the lesion using the tunnel method until it is completely removed; (9) After removing the lesion, treat the wound: use electrocautery to stop bleeding or oozing from the wound; (10) After the operation, the pigs are fasted for 2-3 days. The effectiveness of the model is as follows Figure 2 As shown. Figure 2 The diagram shown in Figure 'a' illustrates a successful modeling of the stenosis, which is needle-like in shape. This group is designated as the post-ESD stenosis group.

[0050] After establishing a large animal (pig) model of esophageal stricture following ESD, endoscopic observation of the wound stricture is performed every 2-4 weeks. If the wound diameter is less than 5 mm, balloon dilation is initiated. Figure 2 (b) Simultaneously record the number of expansions and the animal's weight each time. Approximately 22 weeks after modeling, dissect and collect esophageal tissue for analysis, such as... Figure 2 As shown in Figure c, this is a schematic diagram of the entire esophagus at 22 weeks of age. A distinct stenotic ring is visible. After dissection, in addition to the stenotic ring with intraluminal scar hyperplasia, contracture-like scar changes can also be observed outside the intrinsic muscle layer of the stenotic segment. Figure 2 The figure 'd' shows the narrow, transitional, and normal segments of the esophageal tissue in the circumferential specimen, which will be used for subsequent experiments.

[0051] 1.2 Subsequent drug experiments were conducted, with pigs randomly divided into a linagliptin group (ESD experimental group) and a control group. Pigs in the linagliptin group received 10 mg / head of linagliptin daily via feed for two weeks prior to circumferential ESD, followed by modeling, as described in 1.1. The control group received neither modeling nor linagliptin.

[0052] A schematic diagram of esophageal stricture in the control group at 22 weeks is shown below. Figure 3 As shown in Figure a, the endoscopic modeling diagram of the ESD experimental group who received oral linagliptin (a Dpp4 inhibitor) 10 mg / d two weeks prior to treatment is shown below. Figure 3As shown in b, compared with the ESD post-stenosis group, oral linagliptin significantly alleviated esophageal stricture. After model establishment, endoscopic observation of wound stricture was performed every 2-4 weeks. If the wound diameter was less than 5 mm, the balloon was dilated to 15 mm, and the number of dilations and the animal's weight at each time were recorded. In the linagliptin group, esophageal tissue was dissected and collected for analysis approximately 22 weeks after modeling. Figure 3 As shown in Figure c, this is a schematic diagram of the entire esophagus at 22 weeks, clearly showing a constricting ring. A circumferential specimen was taken at 22 weeks. Figure 3 As shown in d, these are the narrow, transitional, and normal segments of the esophageal tissue in the circumferential specimen, used for subsequent experiments.

[0053] 2. Sequencing analysis

[0054] 2.1 Single-cell sequencing and data analysis were performed by Shanghai Jiayin Biotechnology Co., Ltd., such as... Figure 4 As shown, single-cell sequencing analysis of esophageal tissue in the ESD stenosis group (ESD postoperative stenosis group) showed significantly increased fibroblast expression compared to the blank control group.

[0055] like Figure 5 As shown, single-cell sequencing analysis revealed changes in the proportion of fibroblasts in the esophageal stenosis. Combined with bioinformatics databases (KEGG, GO, and STRING), a DPP-4+ fibroblast subset was identified. Figure 5 In a), this subpopulation of cells is associated with the outer membrane layer. For example... Figure 5 As shown in b, compared with the blank control, the proportion of DPP-4+ subset cells in the stenosis group was significantly increased. Furthermore, sequencing analysis revealed a sharp increase in IL-33+ fibroblasts in the stenotic esophagus compared to the blank control, suggesting an inflammatory immune microenvironment that promotes scar hyperplasia. Figure 5 As shown in c, the expression level of DPP-4+ gene was significantly increased in the narrow group.

[0056] like Figure 6 As shown, single-cell sequencing analysis revealed differences in gene expression between the blank control group and ESD stenosis fibroblasts, as well as the expression characteristics of various fibroblast factors. It was found that ESD stenosis fibroblasts highly expressed CD276, TGFB1, TNFSF9, CXCL10, etc., suggesting changes in the inflammatory immune microenvironment.

[0057] KEGG and HALLMARK analyses of fibroblasts from the blank control group versus ESD stenosis group revealed upregulation of inflammation, apoptosis, IFN-α, and IL-6, further validating that the ESD stenosis group was located in an inflammatory immune microenvironment. Figure 7 ).

[0058] 2.2 Transcript analysis of DPP-4+ subsets via transcriptional network

[0059] The steps are as follows: (1) Co-expression analysis: Identify genes co-expressed with DPP-4 to infer potential transcription factors. (2) Transcription factor-motif enrichment: Use the RcisTarget tool to find enriched transcription factors and their target genes. (3) Regulatory group activity score: Use the AUCell tool to assess the activity of the regulatory group in each cell. (4) SCENIC analysis: Use the SCENIC software package to integrate the above steps to infer the gene regulatory network and cell type. (5) Result visualization: Use the Seurat and pheatmap tools to visualize the activity and differences of the transcription factor regulatory network. Transcripts of the DPP-4+ subset were analyzed by transcription network analysis. In the blank control group vs. the ESD narrow group, TBX21 (Tbet) was significantly increased in the narrow group. Tbet is also an important transforming factor for many immune cells. Through the ChIP-seq database data related to multiple transcription factors such as SRA, GEO, and ENCODE, it was further verified that the transcription factor TBX21 can bind to the DPP-4 promoter and thus upregulate DPP-4. Publicly available ChiP-seq data revealed that TBX21 forms a "Peak" near the DPP-4 promoter and transcription start site. Figure 8 ).

[0060] 2.3. Analyze intercellular communication using R software and corresponding packages.

[0061] The steps are as follows: (1) Cell type labeling: Use tools such as Seurat to perform cluster analysis on single cell data; (2) Ligand-receptor pair analysis: Use the ICELLNET package, a specialized intercellular communication analysis tool, to analyze ligand-receptor interactions between different cell types and calculate their communication scores; (3) Visualize the communication score results to intuitively show the communication strength and patterns between different cell types and perform functional enrichment analysis. Further analysis of the immune cells downstream of the DPP-4+ fibroblast subset showed that it can interact with T cells and macrophages. It mainly works through the three signaling pathways of FGF, NOTCH, and KIT, with the FGF pathway being the most influential on macrophages. Figure 9 ).

[0062] 2.4 Bioinformatics analysis of the DPP-4+ fibroblast subset and its interactions with other cell receptor-ligands revealed that DPP-4+ fibroblasts and macrophages can form receptor-ligand interactions such as COL1A1-CD44 and COL1A family-ITGA1. Figure 10 ).

[0063] 3. The role of DPP-4 inhibitors

[0064] 3.1 We used conventional immunohistochemistry and immunofluorescence assays to analyze the ESD postoperative stenosis group and the ESD experimental group treated with linagliptin.

[0065] like Figure 11 Figure A shows the changes in endoscopic follow-up and dilation every 2-4 weeks after circumferential ESD modeling. The ESD experimental group treated with linagliptin generally only needed 2-3 dilations to stop the stenosis, while the group with post-ESD stenosis required repeated dilations until the end of the entire animal experimental period and remained stenotic. Figure 11 As shown in B, immunohistochemistry confirmed that in addition to the stenotic scar ring originating from the submucosa within the lumen (i.e., the stenotic scar ring within the muscularis propria), the esophageal scar tissue in the ESD postoperative stricture group also included a stenotic scar ring outside the muscularis propria. Compared with the healthy control group, significant scar fibrosis was observed outside the muscularis propria of the esophagus in the ESD postoperative stricture group (as shown by the arrow), suggesting that adventitia scar fibrosis may be deeply involved in the process of refractory esophageal stricture, while linagliptin can significantly inhibit adventitia scar fibrosis after ESD.

[0066] like Figure 12 As shown, immunofluorescence staining was used to analyze and verify the esophageal adventitia (outer ring) of the stenotic segment after ESD.

[0067] Immunofluorescence analysis showed that, compared with the blank control group, the esophageal stricture group after ESD showed significant scar tissue proliferation. COL1A1 (one of the pan-fibroblast markers) staining indicated esophageal fibrosis in the stricture segment.

[0068] like Figure 12 As shown in A, the scar ring outside the muscle layer after ESD was mainly composed of the DPP-4+ subset in the stenosis group. The subsequent intervention with the DPP-4 inhibitor (linagliptin) significantly inhibited the expression of scar hyperplasia in the outer membrane area. Both COL1A1 and DPP-4 were inhibited, especially DPP-4, which was almost not expressed.

[0069] like Figure 12 As shown in Figure B, the intraluminal scar ring is primarily composed of highly expressed IL-33+ subsets. After application of DPP-4 inhibitors, the intraluminal scar tissue was also inhibited to some extent, as evidenced by a significant decrease in both COL1A1 and IL-33. COL1A1 serves as a marker for pan-fibroblasts, while COL15A1 was expressed as homeostatic fibroblasts in the blank control group. This indicates that, under the influence of ESD surgery, homeostatic fibroblasts in the wound cavity mainly transform into the IL33+ subset, while those outside the muscularis propria differentiate into the DPP-4+ subset. In the DPP-4 inhibitor intervention group, the application of linagliptin significantly inhibited DPP-4 expression in the outer membrane layer, thus preventing fibrotic scar changes, and also had a certain inhibitory effect on IL-33 expression in the intraluminal stenotic ring.

[0070] 3.2 Single-cell sequencing analysis of animal experiments with oral DPP-4 inhibitor (linagliptin): blank control group vs. ESD postoperative stenosis group vs. ESD experimental group treated with linagliptin.

[0071] like Figure 13 As shown, after using linagliptin, the proportion of fibroblasts in the linagliptin group (DPP4) relative to the blank control group (D) and the ESD postoperative stenosis group (Cstr) changed significantly. Figure 13 In (a), the proportion of characteristic cell classifications changed significantly. Figure 13 (b) in the example. Figure 13 As shown in c, compared to the DPP-4+ fibroblast subset observed in the ESD stenosis group ( Figure 13 (The cell subsets marked with dashed lines in c) showed that the DPP-4+ subset disappeared in the intervention group. DPP-4 expression was significantly increased in the ESD postoperative stenosis group but significantly decreased in the linagliptin group. Figure 13 (d)

[0072] 3.3 Signal pathway analysis between blank control group vs. ESD postoperative stenosis group vs. ESD experimental group treated with linagliptin.

[0073] The ESD experimental group treated with linagliptin showed significantly lower levels of inflammatory response, apoptosis, and expression of IFN-α and IL-6 compared to the post-ESD stenosis group, suggesting that DPP-4 inhibitors can modulate the immune microenvironment through anti-inflammatory effects. Figure 14 ).

[0074] Compared to the ESD postoperative stenosis group, the DPP-4 inhibitor (linagliptin) intervention group showed a significant increase in myofibroblast marker molecules (MYH11, ACTG2) and a significant decrease in TBX21 transcription factor. Figure 15 This suggests that the immune microenvironment in the intervention group was more stable.

[0075] Compared to the ESD postoperative stenosis group, the DPP-4 inhibitor (linagliptin) intervention group showed a significant disappearance of intercellular interactions in the downstream FGF signaling pathway. Figure 16 The results suggest that DPP-4 inhibitors can inhibit scar hyperplasia.

[0076] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The use of DPP-4 inhibitors in the preparation of drugs for the prevention and / or treatment of gastrointestinal strictures, characterized in that, The DPP-4 inhibitor is linagliptin; The stenosis of the digestive tract refers to stenosis following esophageal ESD.

2. The application according to claim 1, characterized in that, The DPP-4 inhibitor inhibits the formation of fibrotic hyperplasia of the outer membrane scar after ESD.

3. The application according to claim 1, characterized in that, The DPP-4 inhibitor inhibits the expression of DPP-4 in the outer membrane layer.

4. The application according to claim 1, characterized in that, The DPP-4 inhibitor reduces the proportion of DPP-4+ fibroblast subsets.

5. The application according to claim 1, characterized in that, The DPP-4 inhibitor reduces inflammatory response, decreases cell apoptosis, and reduces the expression of IFN-α and IL-6.

6. The application according to claim 1, characterized in that, The DPP-4 inhibitor promotes the expression of myofibroblast marker molecules and reduces the expression of TBX21 transcription factor.

7. The application according to claim 1, characterized in that, The DPP-4 inhibitor reduces cell-cell interactions in the FGF signaling pathway.

8. The application according to claim 1, characterized in that, The drug includes pharmaceutically acceptable excipients.

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