Application of DPP-4 inhibitor in preparation of medicine for preventing and / or treating digestive tract stenosis

Abstract

The invention 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 medicine. On the basis of morphological manifestations of narrow-segment esophageal tissue adventitia scar fibrosis, obvious high expression of DPP-4 < + > fibroblast subgroups in narrow-segment esophageal adventitia fibrosis hyperplasia tissues is found. The DPP-4 inhibitor can be used for preventing and treating intractable stenosis after the esophageal ESD operation through anti-inflammatory and anti-fibrosis effects on esophageal outer tissues of a narrow section, and is a powerful supplement for the stenosis after the esophageal ESD operation focusing on intracavity prevention and treatment of esophageal submucosa and part of innate muscular scar fibrosis at present.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to the use of a DPP-4 inhibitor in the preparation of a medicine for preventing and / or treating digestive tract stenosis. Background Art

[0002] Esophageal endoscopic mucosal dissection (ESD) mainly removes the esophageal mucosal layer and part of the submucosal tissue, while most of the esophageal fibroblasts and fibroblast components are located in the connective tissue, mainly in the submucosal layer and the adventitia layer. After esophageal ESD, the fibroblasts around the wound surface are activated, mainly derived from the submucosal fibroblasts and part of the muscularis propria that are induced to myofibroblasts and inflammatory fibroblasts after damage, which participate in the hyperplasia of esophageal fibrosis scars. During the esophageal repair process after ESD, starting from one week after surgery, the steady-state fibroblasts gradually transform to produce extracellular matrix and induce myofibroblasts and inflammatory fibroblasts. The contraction of myofibroblasts leads to the shrinkage of the esophageal lumen, and inflammatory fibroblasts can induce collagen deposition, thereby leading to scar formation and esophageal stenosis.

[0003] For the research on refractory benign esophageal stricture, whether it is balloon dilatation, radial incision, bougie dilatation, or local or systemic drug application, botulinum toxin injection, epithelial tissue transplantation or stem cell therapy, the direction is based on endoscopic treatment in the esophageal cavity, in order to change the direction of fibrous scar hyperplasia mainly in the submucosal layer through physical or biochemical methods to achieve the purpose of preventing and treating restenosis. However, the role of the outer tissues other than the muscularis propria of the esophagus, especially the fibroblast subsets of the outer membrane in the process of stricture has not received due attention.

[0004] The process of esophageal stenosis after ESD generally includes the following main links: severe inflammatory response, scar fibrosis formation and contracture, collagen deposition, etc. So far, there is still no detailed report on the molecular mechanism 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 are safe for long-term use and easy to take. Currently, there are no reports that DPP-4 inhibitors can inhibit gastrointestinal stenosis. Summary of the invention

[0006] In view of this, an object of the present invention is to provide use of a DPP-4 inhibitor in the preparation of a medicament for preventing and / or treating gastrointestinal stenosis.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] Use of a DPP-4 inhibitor in the preparation of a medicament for preventing and / or treating digestive tract stenosis.

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

[0010] Preferably, the digestive tract stenosis includes esophageal stenosis after ESD surgery.

[0011] Preferably, the DPP-4 inhibitor inhibits the proliferation of adventitial scar fibrosis after ESD surgery.

[0012] Preferably, the DPP-4 inhibitor inhibits the expression of DPP-4 in the adventitial layer.

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

[0014] Preferably, the DPP-4 inhibitor reduces inflammatory response, reduces cell apoptosis, and reduces the expression of IFN-a 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 medicament comprises pharmaceutically acceptable excipients.

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

[0019] The present invention provides the use of DPP-4 inhibitors in the preparation of drugs for preventing and / or treating digestive tract stenosis. Based on the morphological manifestations of scar fibrosis of the outer membrane of esophageal tissue in the stenosis section, the present invention found that the DPP-4+ fibroblast subpopulation in the fibrotic hyperplasia tissue of the outer membrane of the stenosis section was significantly highly expressed. DPP-4 inhibitors can prevent and treat refractory stenosis after esophageal ESD surgery through anti-inflammatory and anti-fibrotic effects on the outer layer tissue of the stenosis section of the esophagus, and are a powerful supplement to the current focus on intraluminal prevention and treatment of scar fibrosis of the esophageal submucosal layer and part of the muscularis propria for stenosis after esophageal ESD surgery. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Schematic diagram of the molecular mechanism of DPP-4 inhibitors in preventing and treating esophageal stenosis after ESD surgery;

[0021] Figure 2Schematic diagram of endoscopic modeling of the stenosis group after ESD surgery; a is a schematic diagram of successful stenosis modeling, with the stenosis being like a needle tip; b is a schematic diagram of balloon dilation to 15 mm if the stenosis diameter is less than 5 mm; c is a schematic diagram of the full length of the esophagus at 22 weeks; d is the stenosis segment, transition segment, and normal segment of the esophageal tissue of the circumferential specimen;

[0022] Figure 3 This is a schematic diagram of endoscopic modeling in the ESD experimental group that took linagliptin (DPP-4 inhibitor) 10 mg / d orally 2 weeks in advance; a is a schematic diagram of esophageal stenosis in the control group; b is a schematic diagram of esophageal stenosis after oral administration of linagliptin, and the esophageal stenosis was significantly relieved; c is a schematic diagram of the full length of the esophagus at 22 weeks; d is the stenosis segment, transition segment, and normal segment of the esophageal tissue of the circumferential specimen;

[0023] Figure 4 Single-cell sequencing analysis of cell population changes (blank control group vs. ESD postoperative stenosis group); a is the esophageal tissue cell population in the ESD postoperative stenosis group (orange population is 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 Single-cell sequencing analysis of the proportion of each subpopulation of proliferative fibroblasts in the blank control group vs. the stenosis group after ESD surgery; a is the esophageal tissue fibroblast population in the stenosis group after ESD surgery (the circle is the DPP-4+ subpopulation); b is the proportion of DPP-4+ subpopulation cells in fibroblasts; c is the DPP-4+ gene expression level in the stenosis group after ESD surgery;

[0025] Figure 6 The single-cell sequencing analysis of differential expression of fibroblast genes and cytokines in the blank control group vs. the stenosis group after ESD surgery; a is a scatter plot of data analysis; b is a statistical integration diagram;

[0026] Figure 7 HALLMARK and KEGG analysis of fibroblasts in the stenotic group of the blank control group vs. those after ESD surgery; a is the result of KEGG analysis; b is the result of HALLMARK analysis;

[0027] Figure 8 Comparison of transcription factor feature analysis between the blank control group and the stenosis group after ESD surgery; a is the transcript of the DPP-4+ subgroup in the transcriptional network analysis; b is the signaling pathway with statistical differences; c is the formation of a "Peak" of TBX21 near the DPP-4 promoter and transcription start site;

[0028] Fig. 9The downstream impact analysis of DPP-4+ subpopulations; a is the close connection between fibroblasts and T cells, macrophages, nerves, and endothelial cells; b is a schematic diagram of the connection between DPP-4+ subpopulation fibroblasts and cells such as T cells and macrophages; c is a schematic diagram of the number of pathways connecting fibroblasts with other cells; d is the correlation strength of multi-ligand pathways in each subpopulation of fibroblasts; e is a schematic diagram of the FGF expression intensity in each subpopulation of fibroblasts;

[0029] Fig.10 The interaction between DPP-4+ fibroblast subpopulation and other cell receptor-ligands;

[0030] Fig.11 Endoscopic animal experiment pictures and immunohistochemical staining results; A is the degree of stenosis and the number of dilations required in the ESD postoperative stenosis group and the ESD experimental group intervened with linagliptin; B is the scar fibrosis hyperplasia in different groups;

[0031] Fig.12 The results of immunofluorescence analysis of the stenosis group after ESD, the blank control group, and the ESD experimental group treated with linagliptin; A is the expression of scar ring hyperplasia outside the muscularis propria, and B is the expression of scar ring hyperplasia inside the cavity;

[0032] Fig.13 The changes in cell subpopulations in the blank control group vs the stenosis group after ESD surgery vs the ESD experimental group intervened with linagliptin; a is the change in the proportion of fibroblasts in the linagliptin group (DPP4) relative to the normal group (D) and the stenosis group (Cstr); b is the change in the proportion of characteristic cell classification after the use of linagliptin; c is the change in the DPP-4+ fibroblast subpopulation (marked by dotted lines); d is the expression of DPP-4 in different groups;

[0033] Fig.14 The figure above shows the HALLMARK and KEGG functional enrichment analysis of the changes in fibroblast signaling pathways after the use of DPP-4 inhibitors; the figure below shows the signaling pathways with statistical differences found based on the above functional analysis;

[0034] Fig.15 The single-cell sequencing analysis of the differences in fibroblast gene and cytokine expression between the blank control group vs the ESD postoperative stenosis group vs the ESD experimental group intervened with linagliptin; the left figure is a data analysis scatter plot; the right figure is a statistical integration diagram;

[0035] Fig.16Single-cell sequencing analysis of changes in downstream cellular pathways of fibroblasts in the blank control group vs ESD postoperative stenosis group vs ESD experimental group intervened with linagliptin; the left picture shows the changes in each cell subpopulation; the middle picture shows the changes in the signaling pathway; the right picture shows the integrated analysis that fibroblasts affect the downstream through the FGF signaling pathway. DETAILED DESCRIPTION

[0036] The present invention provides use of a DPP-4 inhibitor in preparing a medicament for preventing and / or treating digestive tract stenosis. The DPP-4 inhibitor includes sitagliptin, linagliptin, saxagliptin, vildagliptin and alogliptin.

[0037] In the present invention, the digestive tract stenosis includes esophageal post-ESD stenosis. ESD is the preferred option for treating early esophageal cancer, and postoperative stenosis is a common complication. Refractory stenosis is prone to occur after large-area esophageal ESD surgery, which requires regular and repeated endoscopic dilation; the existing treatment options have a high restenosis rate and difficult to control side effects. The present invention found that the stenotic segment of the esophagus has an intraluminal scar ring mainly composed of the submucosal layer and an extraluminal scar ring mainly composed of the esophageal adventitia. Current treatments are mainly intraluminal endoscopic treatments that act on the inner scar ring, while the outer scar ring has not received much attention. The present invention also found that the trauma of large-area ESD surgery of the esophagus led to changes in the inflammatory immune microenvironment in the entire layer of esophageal tissue, with high expression of factors such as CD276, TGFB1, TNFSF-9, CXCL10, IFN-α, IL-6, etc. The inflammatory microenvironment upregulated the TBX21 transcript, which, as a DPP-4 promoter, bound to the nucleus of COL15A1+ steady-state fibroblasts in the esophageal adventitia layer, thereby inducing the transformation of steady-state fibroblasts into a DPP-4+ subpopulation, and then affected downstream immune cells through three significant pathways of FGF, NOTCH, and KIT, among which the FGF pathway affected macrophages the most. DPP-4+ fibroblasts and macrophages could form receptor-ligand interactions such as COL1A1-CD44 and COL1A family-ITGA1, which may further affect downstream collagen deposition and aggravate scar fibrosis of the adventitia tissue of the stenotic segment of the esophagus, which is manifested macroscopically as the clinical status quo of poor endoscopic treatment of refractory esophageal stenosis. The present invention found that DPP-4 inhibitors can effectively prevent and treat esophageal stenosis after ESD surgery. The molecular mechanism diagram is shown in the figure Figure 1 shown.

[0038] In the present invention, the DPP-4 inhibitor inhibits the proliferation of adventitial scar fibrosis after ESD surgery.

[0039] In the present invention, the DPP-4 inhibitor inhibits the expression of DPP-4 in the adventitia layer, and the DPP-4 inhibitor can also inhibit the expression of IL-33 in the intraluminal narrow ring.

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

[0041] In the present invention, the DPP-4 inhibitor reduces inflammatory response, reduces cell apoptosis, and reduces the expression of IFN-a and IL-6. The DPP-4 inhibitor adjusts the immune microenvironment through anti-inflammatory effects.

[0042] In the present 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. The DPP-4 inhibitor inhibits the expression of TBX21 transcription factor and can make the immune microenvironment more stable.

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

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

[0045] In the present 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 are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0047] Example 1

[0048] 1. Constructing animal models

[0049] 1.1 Experimental pigs (weight: 35.2-45.4 kg) were obtained from Shanghai Chedun Experimental Animal Breeding Farm Co., Ltd. In the preliminary experiment, the esophageal ESD model was established: (1) the anal and oral sides of the lesion area were marked first; (2) submucosal injection (normal saline injection, injection volume 10 mL) was performed on the anal side, and a circumferential incision was made from the mucosa to the submucosa along the anal side mark; similarly, submucosal injection (normal saline injection, injection volume 10 mL) was performed on the oral side; (3) intermittent incisions were made on the oral side to form a tunnel opening, and multiple tunnels were established to the anal side circumferential incision, and the tunnel intervals were cut; (4) the oral tunnel was removed. (5) Before establishing the tunnel, perform a circumferential incision under the anal mucosa as the end point of the tunnel; (6) Use Dual knife and IT knife to operate the instrument; (7) After the tunnel is formed in the middle, use an insulated electric knife to expand the tunnel to the left and right sides; (8) Peel off the lesion through the tunnel method until it is completely removed; (9) After removing the lesion, treat the wound surface: electrocautery is used to stop bleeding in the wound area; (10) After the operation, the pigs are fasted for 2 to 3 days. The effectiveness of the model is as follows Figure 2 As shown. Figure 2 The schematic diagram of the successful modeling of the stenosis model is shown in a, and the stenosis is like a needle tip. This is recorded as the post-ESD stenosis group.

[0050] After the large animal (pig) model of esophageal ESD postoperative stricture was established, endoscopic observation of wound stricture was performed every 2-4 weeks. If the wound diameter was less than 5 mm, balloon dilatation ( Figure 2 b), and the number of dilations and the weight of the animals were recorded at the same time. After about 22 weeks of modeling, the esophageal tissues were dissected and collected for analysis. Figure 2 As shown in c, the schematic diagram of the entire length of the esophagus at 22 weeks shows an obvious stenosis ring. After dissection, in addition to the stenosis ring with scar hyperplasia in the cavity, contracture scar-like changes can also be observed outside the muscular layer of the stenosis segment. Figure 2 The circumferential specimen (d) shows the narrow segment, transition segment, and normal segment of the esophageal tissue, which will be used for subsequent experiments.

[0051] 1.2. Subsequent drug experiments were conducted, and the pigs were randomly divided into the linagliptin group (ESD experimental group) and the control group. The pigs in the linagliptin group were given 10 mg / pig of linagliptin per day through feed 2 weeks before circumferential ESD. After continuous administration of linagliptin for 2 weeks, modeling was carried out, and the steps were the same as 1.1. The control group did not undergo modeling treatment and was not given linagliptin.

[0052] Schematic diagram of esophageal stenosis in the control group at 22 weeks Figure 3 As shown in a, the schematic diagram of endoscopic modeling in the ESD experimental group that took 10 mg / d of linagliptin (Dpp4 inhibitor) orally 2 weeks in advance is as follows Figure 3As shown in b, compared with the esophageal stenosis group after ESD, oral linagliptin significantly alleviated esophageal stenosis. After the model was established, endoscopic observation of wound stenosis 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 weight of the animal were recorded. About 22 weeks after the model was established, the esophageal tissue of the linagliptin group was dissected and collected for analysis. Figure 3 As shown in c, the schematic diagram of the entire length of the esophagus at 22 weeks shows a clear stenosis ring. The circumferential specimen was taken at 22 weeks. Figure 3 As shown in (d), the circumferential specimen includes the narrow segment, transition segment, and normal segment of the esophagus, which will be 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. Figure 4 As shown, through single-cell sequencing analysis of esophageal tissue in the ESD stenosis group (ESD postoperative stenosis group), the expression of fibroblasts was significantly increased compared with the blank control group.

[0055] like Figure 5 As shown in the figure, single-cell sequencing was used to analyze the changes in the proportion of fibroblasts in the stricture segment of the esophagus. Combining the bioinformatics databases (KEGG, GO and STRING), it was found that the DPP-4+ fibroblast subpopulation ( Figure 5 In a), this subpopulation of cells is associated with the outer membrane layer. Figure 5 As shown in b, among the fibroblasts, compared with the blank control, the proportion of DPP-4+ subpopulation cells in the stricture group increased significantly, and sequencing analysis found that the number of IL-33+ fibroblasts in the stricture segment of the esophagus increased sharply compared with the blank control group, indicating that it is in an inflammatory immune microenvironment, which promotes scar hyperplasia. Figure 5 As shown in (c), the expression of DPP-4+ gene in the stenosis group was significantly increased.

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

[0057] KEGG and HALLMARK analysis of fibroblasts in the blank control group vs. ESD stenosis group revealed that inflammation, apoptosis, IFN-α, IL-6, etc. in the ESD stenosis group were upregulated, which once again verified that the ESD stenosis group was in an inflammatory immune microenvironment ( Figure 7 ).

[0058] 2.2 Analysis of transcriptomes of the DPP-4+ subpopulation by 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 evaluate the activity of the regulatory group in each cell. (4) SCENIC analysis: Use the SCENIC software package to integrate the above steps to infer gene regulatory networks and cell types. (4) Result visualization: Use Seurat and pheatmap tools to visualize the activity and differences of transcription factor regulatory networks. Through transcriptional network analysis of the transcripts of the DPP-4+ subgroup, the blank control group vs. ESD stenosis group found that TBX21 (Tbet) was significantly increased in the stenosis group. Tbet is also an important transformation 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. Public data ChiP-seq found that TBX21 forms a "Peak" near the DPP-4 promoter and transcription start site ( Figure 8 ).

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

[0061] The steps are as follows: (1) Cell type annotation: Use tools such as Seurat to perform cluster analysis on single-cell data; (2) Ligand-receptor pair analysis: Use the specialized cell-to-cell communication analysis tool ICELLNET package to analyze the ligand-receptor interactions between different cell types and calculate the communication scores between them; (3) Visualize the communication score results to intuitively display the communication intensity and pattern between different cell types and perform functional enrichment analysis. Further analysis of the immune cells affected downstream of the DPP-4+ fibroblast subset showed that it can form an interactive relationship with T cells and macrophages. It mainly acts through the three signaling pathways of FGF, NOTCH, and KIT, among which the FGF pathway is the main one affecting macrophages ( Fig. 9 ).

[0062] 2.4. Bioinformatics analysis of the interaction between DPP-4+ fibroblast subsets and other cell receptors and ligands revealed that DPP-4+ fibroblasts and macrophages can form receptor-ligand interactions such as COL1A1-CD44 and COL1A family-ITGA1 ( Fig.10 ).

[0063] 3. Effects of DPP-4 inhibitors

[0064] 3.1. Routine immunohistochemistry and immunofluorescence analysis were used to analyze the stenosis group after ESD surgery and the ESD experimental group treated with linagliptin.

[0065] like Fig.11 Figure A shows the changes in endoscopic review and dilation every 2-4 weeks after circumferential ESD modeling. The ESD experimental group using linagliptin intervention generally only needed 2-3 dilations before no longer having stenosis, while the post-ESD stenosis group required repeated dilations until the end of the entire animal experiment cycle and still had stenosis. Fig.11 As shown in B, immunohistochemistry confirmed that in addition to the scar stenosis ring originating from the luminal submucosal layer (i.e., the stenosis scar ring within the muscularis propria), the esophageal scar tissue in the stenosis group after ESD surgery also had a stenosis scar ring outside the muscularis propria. Compared with the healthy control group, obvious scar fibrosis and hyperplasia were observed outside the muscularis propria of the esophagus in the stenosis group after ESD surgery (as shown by the arrow), suggesting that scar fibrosis of the adventitia may be deeply involved in the process of refractory esophageal stenosis. Linagliptin can significantly inhibit the hyperplasia of adventitia scar fibrosis after ESD surgery.

[0066] like Fig.12 As shown, the esophageal adventitia (outer ring) of the stricture segment after ESD was analyzed and verified by immunofluorescence labeling.

[0067] Immunofluorescence analysis showed that scar tissue in the stricture group after ESD surgery was significantly increased compared with the blank control group. COL1A1 (a pan-fibroblast marker) staining marked the fibrosis and hyperplasia of the stricture segment of the esophagus.

[0068] like Fig.12 As shown in A, the scar ring outside the muscularis propria in the stenosis group after ESD surgery was mainly composed of the DPP-4+ subgroup. The subsequent addition of the DPP-4 inhibitor (linagliptin) intervention group could significantly inhibit the expression of scar hyperplasia in the adventitial region. Both COL1A1 and DPP-4 were inhibited, especially DPP-4, which was almost not expressed.

[0069] like Fig.12 As shown in B, the intraluminal scar ring is mainly highly expressed by the IL-33+ subgroup. After the application of DPP-4 inhibitors, it can be seen that the intraluminal scar tissue is also inhibited to a certain extent, which is manifested by a significant decrease in COL1A1 and IL-33. COL1A1 is a pan-fibroblast marker, and COL15A1 is expressed as steady-state fibroblasts in the blank control group. It can be seen that under the influence of ESD surgery, the steady-state fibroblasts in the wound surface are mainly transformed into the IL33+ subgroup in the cavity, and differentiated into the DPP-4+ subgroup outside the muscularis propria. The use of linagliptin in the DPP-4 inhibitor intervention group can significantly inhibit the anti-fibrotic scar changes of DPP-4 expression in the outer membrane layer, and also has a certain inhibitory effect on the expression of IL-33 in the intraluminal stenosis ring.

[0070] 3.2. Single-cell sequencing analysis was performed after animal experiments on oral DPP-4 inhibitors (linagliptin): blank control group vs ESD postoperative stenosis group vs ESD experimental group intervened with linagliptin.

[0071] like Fig.13 As shown in Figure 2, after using linagliptin, the proportion of fibroblasts in the linagliptin group (DPP4) changed significantly compared with the blank control group (D) and the stenosis group after ESD surgery (Cstr). Fig.13 In a), the proportion of characteristic cell classification changes significantly ( Fig.13 b) Fig.13 As shown in c, compared with the DPP-4+ fibroblast subpopulation in the ESD stenosis group ( Fig.13 The cell subpopulation marked by the dotted line in c) disappeared in the intervention group. The expression of DPP-4 was significantly increased in the stenosis group after ESD but decreased significantly in the linagliptin group ( Fig.13 d) in.

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

[0073] Compared with the stenosis group after ESD, the inflammatory response, cell apoptosis, IFN-a and IL-6 expression in the ESD experimental group treated with linagliptin were significantly decreased, suggesting that DPP-4 inhibitors can reduce inflammation and adjust the immune microenvironment. Fig.14 ).

[0074] Compared with the stenosis group after ESD, the myofibroblast marker molecules (MYH11, ACTG2) in the DPP-4 inhibitor (linagliptin) intervention group increased significantly, while the TBX21 transcription factor decreased significantly ( Fig.15 ), suggesting that the immune microenvironment of the intervention group was more stable.

[0075] Compared with the stenosis group after ESD, the cell-cell interaction of the downstream FGF signaling pathway was significantly lost in the DPP-4 inhibitor (linagliptin) intervention group ( Fig.16 ), suggesting that DPP-4 inhibitors can inhibit scar hyperplasia.

[0076] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of DPP-4 inhibitors in the preparation of drugs for preventing and / or treating gastrointestinal stenosis.

2. The use according to claim 1, characterized in that: The DPP-4 inhibitors include sitagliptin, linagliptin, saxagliptin, vildagliptin and alogliptin.

3. The use according to claim 1, characterized in that: The digestive tract stricture includes esophageal stricture after ESD surgery.

4. The use according to claim 1, characterized in that: The DPP-4 inhibitor inhibits the proliferation of adventitial scar fibrosis after ESD surgery.

5. The use according to claim 1, characterized in that: The DPP-4 inhibitor inhibits the expression of DPP-4 in the adventitial layer.

6. The use according to claim 1, characterized in that: The DPP-4 inhibitor reduces the proportion of DPP-4+ fibroblast subpopulation.

7. The use according to claim 1, characterized in that: The DPP-4 inhibitor reduces inflammatory response, reduces cell apoptosis, and reduces the expression of IFN-a and IL-6.

8. The use 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.

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

10. The use according to claim 1, characterized in that: The drug includes pharmaceutically acceptable excipients.

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