Application of OXTR agonist in preparation of medicine for treating nasosinusitis

Abstract

The invention belongs to the technical field of biological medicine, and relates to application of an OXTR agonist in preparation of a medicine for treating chronic sinusitis (CRS) and respiratory ciliary injury. CRS is treated based on targeted OXTR, and it is found that the OXTR agonist has an excellent treatment effect on promotion of nasal mucosa cilia regeneration and improvement of chronic sinusitis and can promote cilia repair, reduce infiltration of neutrophils and eosinophils and improve the inflammatory environment. In addition, an intranasal treatment dosage form aiming at OXTR is already applied to clinical application of nervous system diseases, the clinical application range of the medicine is expanded, practical feasibility is achieved by improving a better dosage form, and good industrialization prospects are achieved.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine technology and relates to the use of OXTR agonists in preparing drugs for treating sinusitis and respiratory tract cilia damage and promoting cilia regeneration. Background Art

[0002] Chronic rhinosinusitis (CRS) is a common chronic inflammatory condition of the mucosa, affecting more than 10% of the general population. However, hypoxia, microbial products, and proinflammatory mediators produced during chronic inflammation lead to ciliary dysfunction and loss through direct toxic effects on cilia, and result in aggravated inflammation of the nasal mucosa and infiltration of inflammatory cells. Downregulation of the key ciliary differentiation gene FOXJ1 and its abnormal localization during nasal epithelial re-epithelialization may contribute to impaired cilia formation and motility in CRS. Mutations in DNAH1, DNALI1, DNAH5, MNS1, or DNAI1 result in defects in the dynein arms, leading to impaired ciliary motility. Ciliated cell loss and dysfunction are also present not only in CRS, but also in respiratory diseases such as allergic rhinitis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia, and cystic fibrosis. Invasive treatments such as surgery and radiotherapy can impair ciliated cell function. These alterations impair mucus clearance, leading to an increased risk of disease progression due to biofilm formation, chronic infection, and other environmental factors. Therefore, promoting the repair of ciliated cells has become a promising therapeutic strategy, not only in CRS but also in the treatment of other respiratory diseases.

[0003] G protein-coupled receptors (GPCRs) are a large class of cell surface receptors that participate in a variety of biological processes that are critical for the development of diseases. Therefore, GPCRs are the main focus of drug target research and are very suitable for therapeutic intervention. Oxytocin receptor (OXTR) belongs to the GPCR superfamily and is widely expressed in various organs. Oxytocin (OT) is its main ligand. The OT / OXTR signaling pathway plays a vital role in cell proliferation and differentiation in multiple systems such as neural dendrite growth, adipogenesis, and cardiomyocyte differentiation. In addition, OT can also improve neurological diseases by regulating neuronal pyroptosis, oxidative stress, inflammation, and excessive mitochondrial fission. However, its function in respiratory diseases, especially CRS, and its role in the progression of CRS are still unclear. Through single-cell analysis of CRS nasal mucosa and polyp tissues, we found that OXTR was specifically expressed in nasal mucosal ciliated cells, and it is speculated that it plays a key role in the differentiation, maturation, epithelial barrier protection, and inflammation regulation of ciliated cells. Summary of the invention

[0004] In response to the above clinical problems, the present invention discovered that oxytocin receptor (OXTR) is an effective target for chronic rhinosinusitis (CRS). Cell experiments and animal experiments confirmed that after OXTR knockdown, the number of differentiated and mature ciliated cells decreased. After intervention with OXTR agonists, the maturation and regeneration of ciliated cells were significantly promoted, and the inflammatory environment of CRS was improved, indicating that OXTR agonists have a therapeutic effect on CRS. At the same time, in the nasal mucosal injury model, the regeneration of ciliated cells was also significantly promoted.

[0005] Specifically, the technical solution of the present invention is as follows:

[0006] The use of OXTR agonists in the preparation of drugs for treating diseases related to respiratory mucociliary and epithelial barrier damage or aplastic disorders. Including: the use of OXTR agonists in the preparation of drugs for promoting the regeneration of respiratory mucociliary and epithelial barriers, and the use of OXTR agonists in the preparation of drugs for reducing respiratory mucociliary and epithelial barrier damage.

[0007] Furthermore, the diseases related to damage or aplastic disorders of the respiratory mucosal cilia and epithelial barrier include respiratory diseases such as sinusitis, nasal polyps, allergic rhinitis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia and cystic fibrosis.

[0008] The use of OXTR agonists in the preparation of drugs for treating sinusitis. Further, the use of OXTR agonists in the preparation of drugs for treating chronic sinusitis.

[0009] Use of OXTR agonists in the preparation of drugs for preventing sinusitis.

[0010] The drug for treating and / or preventing sinusitis of the present invention is used to reduce inflammation of the nasal mucosa, and the sinusitis includes chronic sinusitis. Further, the chronic sinusitis includes (1) chronic rhinosinusitis without nasal polyps (CRSsNP); (2) chronic rhinosinusitis with nasal polyps (CRSwNP).

[0011] The OXTR agonist includes but is not limited to any substance that has been reported to activate OXTR.

[0012] Furthermore, the OXTR agonists include the following that have the function of directly or indirectly activating the oxytocin receptor:

[0013] a) Peptides of synthetic or natural origin, including oxytocin and its derivatives;

[0014] b) small molecule compounds, including organic compounds and pharmaceutically acceptable salts, prodrugs, solvates, co-crystals, and isotope-labeled substances thereof;

[0015] c) antibodies or antigen-binding fragments thereof, including single-chain antibodies, nanobodies, and bispecific antibodies;

[0016] d) Nucleic acid aptamers and gene-encoded protein activators;

[0017] Furthermore, the OXTR agonist includes but is not limited to at least one of carbetocin, oxytocin, TGOT, LIT-001, RG7314, TC OT 39, PF-06655075, WAY267464, OT-12, and carbetocin metabolites.

[0018] Preferably, the OXTR agonist is carbetocin and its acetate.

[0019] Preferably, the OXTR agonist is oxytocin and its acetate.

[0020] Preferably, the OXTR agonist is compound formula I described in CN201580027370.7.

[0021] Preferably, the OXTR agonist is a compound of formula I, formula II, or formula III described in CN201480004903.5.

[0022] Preferably, the OXTR agonist is a commercially available OXTR activating drug, including oxytocin (oxytocin nasal spray, Oxytocin Nasal Spray).

[0023] The use of the OXTR agonist of the present invention in the preparation of a drug for treating sinusitis includes: the OXTR agonist is delivered and administered through the nasal cavity to treat CRS. Preferably, the treatment of CRS includes but is not limited to repairing damaged ciliary cells and inhibiting inflammation caused by CRS.

[0024] The present invention also provides a pharmaceutical preparation, which comprises the above-mentioned drug for treating sinusitis with the OXTR agonist as an active ingredient, combined with a pharmaceutically acceptable diluent or carrier.

[0025] The pharmaceutical preparation achieves one or more of the following effects by activating OXTR: treating sinusitis inflammation, reducing neutrophil and eosinophil infiltration, improving nasal barrier integrity damage, and reducing ciliated cell damage.

[0026] The administration method of the pharmaceutical preparation includes: at least one of nasal administration, transdermal administration, oral administration, and intravenous administration; the dosage form of the pharmaceutical preparation includes at least one of nasal drops, sprays, inhalation aerosols, tablets, capsules, injections, oral liquids, and granules.

[0027] Furthermore, the pharmaceutical preparation achieves the following therapeutic functions by activating OXTR:

[0028] (a) Inhibit the expression of inflammatory markers such as IL-1β, TNF-α and MPO in the sinus mucosa, and reduce neutrophil infiltration;

[0029] (b) Promote the regeneration of nasal mucosal cilia, including repairing damaged ciliary cells and restoring ciliary cell function.

[0030] In terms of specific use, the OXTR agonist for preparing a drug for treating sinusitis described in the present invention can be used alone or together with many other chemical substances. Regardless of whether these chemical substances have biological activity or have the function of treating diseases, including auxiliary functions such as synergistic amplification, antagonism or alleviation of side effects of the OXTR agonist drug for preparing a drug for treating sinusitis, these chemical substances include pharmaceutically acceptable diluents or carriers, including one or more of food, natural products, chemically synthesized drugs or human drug delivery systems, etc.; preferably include one or more of pharmaceutically acceptable diluents, carriers or foods; and more preferably pharmaceutically acceptable carriers.

[0031] As used herein, "pharmaceutically acceptable diluents or carriers" include any and all physiologically suitable solvents, dispersion media, placenta, antibacterial and antifungal agents, isotonic agents or absorption delaying agents, etc., and include one or more of water, saline, phosphate buffered saline, glucose, glycerol or ethanol, etc. and combinations thereof. Preferably, the diluent is an isotonic agent, including one or more of sugars, mannitol, sorbitol, sorbitol polyols or sodium chloride. Pharmaceutically acceptable carriers also include a small amount of auxiliary substances, such as one or more of wetting agents or emulsifiers, preservatives or buffers, etc., which are used to enhance the shelf life or efficacy of the OXTR agonist or its pharmaceutical preparation.

[0032] The beneficial effects of the present invention are:

[0033] (1) Providing OXTR agonists to target OXTR can repair ciliated cells and reduce the infiltration of neutrophils and eosinophils. Experiments have confirmed that OXTR agonists are very effective in inhibiting the pathological symptoms of sinusitis, including relieving inflammation, improving damage to the integrity of the nasal barrier, and promoting the regeneration of nasal cilia.

[0034] (2) Providing OXTR agonists to target OXTR can achieve rapid repair and regeneration of the nasal mucosal ciliary cell epithelial injury model.

[0035] (3) The agonist corresponding to the therapeutic target of the present invention is already clinically known as a nasal spray, which has good industrial prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0037] Figure 1 Immunofluorescence staining of primary human mucosal epithelial ciliated cells cultured at air-liquid interface (ALI). The expression of ciliated cells (β-IV-tubulin) and ciliated cell early transcription factor (FOXJ1) was significantly reduced in the OXTR knockdown group. NC represents the negative control group, and sh-OXTR represents the OXTR knockdown group.

[0038] Figure 2 Scanning electron microscopy of ALI cultured ciliated cells. NC represents the negative control group, and sh-OXTR represents the OXTR expression knockdown group. The cilia in the knockdown group were significantly reduced and morphologically abnormal.

[0039] Figure 3 Immunofluorescence staining of ALI cultured ciliated cells. IL-13 intervention led to a significant decrease in the expression of ciliated cells (β-IV-tubulin) and ciliated cell early transcription factor (FOXJ1), while oxytocin (OT) treatment improved ciliated cell destruction under inflammatory conditions. CON represents the control group, IL-13 represents the IL-13 treatment group, and IL-13+OT represents the simultaneous administration of IL-13 and OT intervention.

[0040] Figure 4 For SO 2 HE staining of the nasal mucosa of the mouse model of exposed nasal mucosa damage shows that the cilia morphology is more complete after intervention with carbetocin (Carb, OXTR agonist) than natural restoration. 2 Represents natural recovery mice after exposure, SO 2 +Carb represents mice that received Carb intervention after exposure.

[0041] Figure 5 For SO 2 Immunofluorescence (IF) staining of the nasal mucosa of the exposed nasal mucosal damage mouse model showed that the expression of key transcription factors and markers of ciliary cells FOXJ1 was significantly increased after Carb intervention compared with natural repair.

[0042] Figure 6HE staining of mouse nasal mucosa showed that the destruction of ciliary cells was significantly improved after Carb intervention compared with the CRS group. CON was the control group, CRS was the papain (PAP)-induced CRS model group, and Carb was the CRS model mice treated with Carb at the same time.

[0043] Figure 7 RT-qPCR detection found that Carb can promote the expression of OXTR and FOXJ1 mRNA in the nasal mucosa of CRS model mice.

[0044] Figure 8 The nasal mucosa staining of PAP-induced CRS model mice showed that the expression of FOXJ1 was significantly increased after Carb intervention compared with the CRS group.

[0045] Fig. 9 ELISA test found that Carb can reduce the expression of neutrophil-related inflammatory factors in the nasal lavage fluid (NALF) of CRS model mice. CON is the control group, CRS is the LPS-induced neutrophil infiltration type CRS model group, and CRS+Carb is the CRS model mice given Carb intervention group at the same time.

[0046] Fig.10 PAS staining showed that Carb could reduce the proliferation of goblet cells in the nasal mucosa of CRS mice.

[0047] Fig.11 Immunofluorescence staining showed that Carb could reduce the infiltration of neutrophils in the nasal mucosa of CRS mice. DETAILED DESCRIPTION

[0048] In order to enable those skilled in the art to better understand the present application, the present application is further explained in conjunction with specific implementation methods.

[0049] Unless otherwise specified, the raw materials or reagents used in the examples of the present invention are commercially available products.

[0050] The percentages used in the embodiments of the present invention are all by mass unless otherwise specified.

[0051] In some embodiments of the present invention, cells were cultured in an air-liquid interface differentiation model to explore the differentiation effect of OXTR on ciliated cells. The number of ciliated cells decreased after differentiation of the OXTR knockdown group, and the cilia were short and sparse under the electron microscope. In vitro administration of the OXTR agonist OT significantly improved IL-13-induced ciliated cell damage.

[0052] Use SO 2 Inducing nasal mucosal ciliary cell damage in mice, this model was used to explore the role of OXTR in ciliary cell repair. Intervention with OXTR agonists accelerated the repair and regeneration of ciliary cells.

[0053] Two chronic sinusitis mouse models induced by papain and LPS were used to explore the therapeutic effect of OXTR on chronic sinusitis (CRS). In the CRS group, ciliary cell destruction was obvious, accompanied by neutrophil infiltration and increased inflammatory factors, while intervention with OXTR agonists reduced ciliary destruction, significantly reduced neutrophil infiltration, and significantly downregulated inflammatory factors.

[0054] In some embodiments of the invention, the OXTR agonist (preferably carbetocin and oxytocin) will be provided as a pharmaceutical formulation in a single dose, multiple doses may be provided over a period of time, and the dose will be achieved in the form of a concentration of the total volume, so that the dose will be 80 IU / ml, 160 IU / ml, 240 IU / ml or more, depending on the therapeutic effect. In other embodiments, administration will be carried out at a ratio of the mass of the OXTR agonist to the mass of the individual treated, so that the dose will be 10 IU, 20 IU, 40 IU or more, depending on the therapeutic effect. In multiple administration embodiments, the dosing regimen may be 1 dose / day, 2 doses / day, 3 doses / day or more, and may continue for the necessary time, so that administration may continue for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 20 weeks, or permanently during the life of the organism.

[0055] In the embodiments of the present invention, all statistical data were calculated using GraphPad Prism software. Two-group comparisons were performed using t-test. Multiple-group comparisons were performed using one-way analysis of variance. Results were expressed as mean ± standard error of the mean (SEM). p < 0.05 was considered statistically significant.

[0056] Example 1

[0057] Cell culture and intervention: Human primary nasal epithelial cells (HNECs) were collected from inferior turbinate (IT) or nasal polyp (NP) tissues by scraping with a nasal probe. HNECs were cultured in bronchial epithelial cell culture medium (ScienCell, 3211, USA) and collagen-coated 6-well plates (Gibco, A1142801, USA) for one week before being used in subsequent experiments. After the epithelial cells filled the 6-wells, they were passaged and transfected with lentiviral vectors (pLV-hU6-human OXTR_shRNA-CMV-Puro, pLV-hU6-NC shRNA-CMV-Puro, SyngenBio) according to the manufacturer's instructions. After 48 hours, puromycin (2 μg / mL, ST551, Beyotime) was added to screen the successfully transfected cells. The screening was continued for 5-7 days, and the surviving cells were cultured and expanded. They were then transferred to chamber culture plates (TCS016012, BIOFIL). Subsequently, differentiation medium (BEpiC:DMEM / F12=1:1) was used for air-liquid interface (ALI) culture. The medium was changed every 2-3 days, and the differentiation period was 31-35 days. ALI-differentiated HNECs were divided into control group, model group and treatment group. The model group was treated with IL-13 (HY-P72795, MCE), and the treatment group was treated with IL-13 and OT at the same time. Example 2 Experimental materials: Oxytocin (OT) / Carbetocin (Carb), derived from biochemical synthesis; PAP, papain extract (Sigma-Aldrich, P5306-25MG, USA); LPS (lipopolysaccharide, Sigma-Aldrich, USA), phosphate buffered saline (PBS, B310KJ, source culture), bronchial epithelial cell culture medium (3211, ScienCell), IL-13 recombinant protein (HY-P7033, MCE), rat tail collagen (A1142801, Gibco)

[0058] Animal model construction and intervention: PAP-induced CRS mouse model was established. C57 mice, male, 6-8 weeks old, weighing 18-20 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The mice were housed in an SPF constant temperature animal room (temperature: 23+2°C, relative humidity: 55±10%, light-dark cycle 12h), and the model was established after 3 days of isolation and adaptive feeding. Mice in the CRS group were intranasally administered 20 μg of papain (Sigma-Aldrich, P5306-25MG, USA) dissolved in 20 μL phosphate buffered saline (PBS) (10ul / side) on days 0-2 and 7-11. At the same time, the control group was treated nasally with an equal amount of heat-inactivated (95°C, 30 minutes) papain dissolved in 20 μL PBS. This method was based on previous studies, and no adverse health effects, such as weight loss or changes in water or food intake, were observed at the 11th day. During this period, the model group was given PBS (20ul) and the treatment group was given carbetocin intervention (20μg / 20μL). All mice were killed 24 hours after the last treatment for subsequent experiments.

[0059] The LPS-induced CRS mouse model was established. The control group: 20 μL PBS was intranasally administered 3 times a week for 2 consecutive months. The model group: mice were intranasally administered 20 μg / 20 μL LPS solution (diluted with PBS) in the same way. The treatment group: starting from day 31, carbetocin (20 μg / 20 μL) was intranasally administered 30 minutes after LPS stimulation. All animals were humanely killed 24 hours after the last treatment.

[0060] Create SO 2 In the induced ciliary cell injury model, mice were placed in a sealed exposure chamber and received SO 2 Gas (500 ppm) was exposed for 4 hours. The chamber was equipped with a ventilation system to regulate airflow and ensure consistent exposure. After sulfur dioxide exposure, the subjects were randomly divided into a control group and a treatment group and given PBS or Carb (20 μg / 20 μL) for 5 days.

[0061] Collection and detection of nasal mucosal tissue sections: The experimental mice after modeling were anesthetized, and the mouse heads were cut off after cardiac perfusion with 4% paraformaldehyde tissue fixative, and the excess muscles and connective tissues were removed, while the nasal and sinus tissues were completely preserved. The sections were fixed with 4% paraformaldehyde tissue fixative for 24 h, decalcified with EDTA decalcification solution until osteomalacia (14 days), dehydrated with 15%-30% sucrose solution gradient (24-48 h), embedded in paraffin and sections were observed by H&E staining and immunofluorescence.

[0062] ELISA test: Take out the supernatant sample of mouse nasal lavage fluid and thaw it on ice. According to the reagent instructions, add the standard and sample in sequence, and then detect the absorbance on the machine after adding enzyme, incubation, washing, color development, termination and other steps to calculate the sample concentration.

[0063] Immunofluorescence staining: Block nonspecific binding with blocking buffer (5% BSA + 2% goat serum + 0.5% Triton X-100) at room temperature for 60 minutes, add primary antibody, and incubate overnight at 4°C. The primary antibodies used in this study are: β-IV-tubulin (R23621, ZENBIO, 1:500), FOXJ1 (14-9965-82, Invitrogen, 1:200) MPO (AB208670, abcam, 1:200), MBP (DF6992, Affinity Biosciences, 1:200). Wash the samples three times with TBST to remove unbound primary antibodies and incubate with secondary antibodies at room temperature for 1 hour. After washing the slides, stain with DAPI (C0065, Solarbio) at RT in the dark for 10 minutes. Use anti-fluorescence quencher (S2100, Solarbio) for further evaluation after sealing.

[0064] Experimental results:

[0065] The key role of OXTR in the differentiation of ciliated cells was explored by using human nasal epithelial primary cells differentiated by air-liquid interface (ALI). After OXTR knockdown, the fluorescence area of ​​β-IV-tubulin (relative ratio 0.5988±0.03144) and the expression of FOXJ1 (relative ratio 0.5925±0.07113) of the ciliary marker were significantly reduced compared with the control group, indicating that the loss of OXTR leads to a slowdown in the differentiation of ciliated cells ( Figure 1 ). Scanning electron microscopy observation of cilia ultrastructure further revealed that ALI human nasal epithelial primary cells with OXTR gene knockout showed severe cilia defects. Compared with the cilia in the control group, the cilia structure after OXTR knockout appeared to be small and short, indicating that OXTR deficiency led to abnormal differentiation and functional loss of ciliated cells ( Figure 2 ). OT intervention can significantly improve the IL-13-induced β-IV-tubulin fluorescence area and FOXJ1 + The decrease of cells Figure 3 ).

[0066] Use SO 2 A ciliary cell injury model was established to explore the effect of OXTR agonists on ciliary cell repair in a non-inflammatory environment. HE staining showed that the ciliary morphology of the nasal mucosa of mice in the Carb intervention group was more complete than that in the control group (natural repair) ( Figure 4Further immunofluorescence staining revealed that carbetocin promoted the expression of FOXJ1 in damaged ciliated cells (p=0.0430) ( Figure 5 ), indicating that intranasal administration of OXTR receptor stimulation can accelerate the repair of ciliary cells.

[0067] The papain-induced CRS mouse model was used to explore the effect of OXTR agonists on ciliated cells in chronic sinusitis. HE observed the morphology and degree of damage of ciliated cells in the nasal mucosa of mice and found that the ciliated cells in the model group were significantly damaged, with shedding and morphological changes. Carbetocin can effectively improve the morphology of ciliated cells under inflammatory conditions ( Figure 6 ). Further qPCR detection found that carbetocin could promote the expression of OXTR (p<0.0001) and FOXJ1 mRNA in the nasal mucosa of CRS model mice (p<0.0001) ( Figure 7 Immunofluorescence staining showed that carbetocin promoted the expression of FOXJ1 in ciliated cells under inflammatory conditions (p=0.0020), indicating that OXTR agonists can promote the repair of ciliated cells under inflammatory conditions ( Figure 8 ).

[0068] Using the LPS-induced CRS mouse model, the improvement of the inflammatory environment of chronic sinusitis by OXTR agonists was investigated. ELISA test found that after Carb intervention, the neutrophil-related inflammatory factors IL1-β (74.42pg / ml vs. 11.74ppg / ml), CXCL1 (111.7pg / ml vs. 33.08pg / ml), TNF-α (107.9pg / ml vs. 36.24pg / ml), G-CSF (391.1pg / ml vs. 23.17pg / ml), and IL6 (7.642 vs. 1.389pg / ml) in NALF were significantly lower than those in the model group ( Fig. 9 ). PAS staining showed that goblet cell proliferation was significantly reduced after Carb intervention compared with the model group ( Fig.10 ), immunofluorescence staining showed that the expression of Mpo after Carb intervention was significantly lower than that in the model group, indicating that neutrophil infiltration was significantly reduced in the Carb intervention group and CRS was significantly alleviated ( Fig.11 ).

Claims

1. Application of OXTR agonists in the preparation of drugs for treating sinusitis.

2. Application of OXTR agonists in the preparation of drugs for preventing sinusitis.

3. Application of OXTR agonists in the preparation of drugs that promote regeneration of respiratory mucociliary and epithelial barriers.

4. Application of OXTR agonists in the preparation of drugs for reducing damage to respiratory mucociliary and epithelial barriers.

5. The use according to any one of claims 1 to 4, characterized in that: The OXTR agonists include the following that have the function of directly or indirectly activating the oxytocin receptor: a) Peptides of synthetic or natural origin, including oxytocin and its derivatives; b) Small molecule compounds, including organic compounds and pharmaceutically acceptable salts, prodrugs, solvates, co-crystals, and isotope-labeled compounds thereof; c) Antibodies or antigen-binding fragments thereof, including single-chain antibodies, nanobodies, and bispecific antibodies; d) Nucleic acid aptamers and gene-encoded protein activators.

6. The use according to claim 5, characterized in that The OXTR agonist includes at least one of carbetocin, oxytocin, TGOT, LIT-001, RG7314, TC OT 39, PF-06655075, WAY267464, and OT-12.

7. The use according to any one of claims 1 to 4, characterized in that: The application includes: OXTR agonist is delivered and administered via nasal cavity to treat chronic sinusitis.

8. A pharmaceutical preparation, characterized in that It comprises a drug as defined in any one of claims 1 to 4, in combination with a pharmaceutically acceptable diluent or carrier.

9. The pharmaceutical preparation according to claim 8, characterized in that The pharmaceutical preparation achieves one or more of the following effects by activating OXTR: treating sinusitis inflammation, reducing neutrophil and eosinophil infiltration, improving nasal barrier integrity damage, and promoting nasal mucosal cilia regeneration.

10. The use according to any one of claims 1 to 4, characterized in that: The administration method of the drug includes at least one of nasal administration, transdermal administration, oral administration, and intravenous administration; The drug dosage form for nasal administration includes at least one of nasal drops, sprays, inhalation aerosols, oral preparations and intravenous preparations.

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