CN117379535B - Application of hepatocyte growth factor in preparing medicine for allergic rhinitis - Google Patents
Application of hepatocyte growth factor in preparing medicine for allergic rhinitis Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides application of hepatocyte growth factor in preparing a medicament for allergic rhinitis, and relates to the technical field of biology. The hepatocyte growth factor can relieve symptoms of allergic rhinitis of a subject, relieve inflammatory cell infiltration and goblet cell proliferation of nasal mucosa of a tested animal of the allergic rhinitis, and enrich treatment means of the allergic rhinitis.
Description
Technical Field
The invention relates to the field of biotechnology, in particular to application of hepatocyte growth factor in preparing medicines for allergic rhinitis.
Background
Allergic rhinitis (Allergic Rhinitis) is a popular but not well-known inflammatory disease of the nasal mucosa characterized by itching, sneezing, runny nose and nasal congestion. It is mediated by early and late hypersensitivity reactions to indoor and outdoor environmental allergens, similar to allergic asthma. It is often overlooked, diagnosed inadequately, misdiagnosed and not valued, which not only jeopardizes health, but also causes an increase in social costs. Although allergic rhinitis is not a serious disease, it has significant clinical implications, as it is the basis for many complications, is a major risk factor for poor asthma control, and affects quality of life, work or learning efficiency. Global prevalence of allergic rhinitis has steadily increased since the 60 s of the 20 th century. Currently, the prevalence of allergic rhinitis in children is estimated to be 5% -15%, and adults 10% -40%. Allergic rhinitis belongs to allergic diseases of the respiratory tract and is essentially type I allergic reaction. However, the occurrence and development of allergic rhinitis inherently involve complex pathological mechanisms, and the current research progress has not found related drugs or technologies capable of thoroughly treating allergic rhinitis.
Currently, drug therapy is the basic intervention for allergic rhinitis. First-line drug regimens including nasal glucocorticoids, nasal or oral second-generation histamine receptor antagonists, oral leukotriene receptor antagonists, and the like, all improve the clinical symptoms of allergic rhinitis patients in the acute episode stage to varying degrees. In addition, immunotherapy is also a first-line treatment method for allergic rhinitis, including subcutaneous immunotherapy and sublingual immunotherapy, in which patients are given stepwise increasing doses of allergen extracts (therapeutic vaccines), which induce immune tolerance in the body, so that a part of patients who are in compliance with the indications experience significant relief of symptoms, even without clinical symptoms, upon re-exposure to the corresponding allergen. Antihistamines, however, are associated with sedation, bradykinesia, and decreased learning performance.
The existing drug treatment scheme can control symptoms, but can not turn into an immune imbalance state of the nasal mucosa local part and/or the whole body of a patient with allergic rhinitis, so that the symptoms of the allergic rhinitis often repeatedly occur and persist, the potential risk of secondary or concurrent asthma is increased, the life quality and compliance of the patient are greatly reduced, and the burden of the patient and a medical system is increased. In addition, guideline-directed medication is ineffective for up to 20% of allergic rhinitis patients.
Although immunotherapy is aimed at the treatment of IgE-mediated type I allergic diseases, the immunotherapy has the problems of narrow applicable population, long treatment period, low standardization level and the like. In particular, this is determined by its specific therapeutic mechanism. At present, immunotherapy is only suitable for patients allergic to house dust mites, dust mites and artemisia annua pollen, and the patients allergic to house dust mites, dust mites and artemisia annua pollen are required to be combined with a small amount of other allergens (1-2), and preferably patients allergic to single dust mites or artemisia pollen. Immunotherapy is generally divided into two phases, dose accumulation and dose maintenance, with a total course of treatment of 3 years and a considerably longer treatment period. In addition, the dose and concentration units of allergen vaccines produced by different manufacturers aiming at different allergens are not unified, the curative effect and the safety of the allergen vaccines are different, and the treatment schemes are different. The above problems greatly limit the application of immunotherapy in daily therapeutic work. Thus, there is a need to explore innovative, effective, safe treatments.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide the application of hepatocyte growth factor in preparing medicines for treating and/or relieving allergic rhinitis so as to improve the treatment means of the allergic rhinitis.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention provides application of hepatocyte growth factor as a therapeutic agent in preparing a medicament for treating and/or relieving allergic rhinitis.
In alternative embodiments, the agent comprises a hepatocyte growth factor protein or comprises a polynucleotide encoding a hepatocyte growth factor.
In an alternative embodiment, the hepatocyte growth factor is a human hepatocyte growth factor.
In an alternative embodiment, the medicament is in the form of an injection or nasal preparation.
In an alternative embodiment, the medicament is for use in a mammal.
In an alternative embodiment, the medicament further comprises at least one of a pharmaceutically acceptable adjuvant, carrier, delivery formulation, and recombinant cell expressing hepatocyte growth factor.
In alternative embodiments, the method for treating and/or alleviating allergic rhinitis comprises reducing inflammatory cell infiltration of nasal mucosa.
In an alternative embodiment, the inflammatory cells include at least one of eosinophils, neutrophils, basophils, lymphocytes and macrophages.
In alternative embodiments, the inflammatory cells include eosinophils and lymphocytes.
In alternative embodiments, the method for treating and/or alleviating allergic rhinitis comprises alleviating proliferation of goblet cells of nasal mucosa.
Compared with the prior art, the invention has the following beneficial effects:
the present invention provides the discovery that hepatocyte growth factor can alleviate symptoms of allergic rhinitis in a subject, including reducing animal behavioral scores of a subject animal with respect to allergic rhinitis, reducing inflammatory cell infiltration and goblet cell proliferation in nasal mucosa of a subject animal with allergic rhinitis. Based on the findings, the application of the hepatocyte growth factor provided by the invention as a therapeutic agent in preparing the medicament for treating and/or relieving the allergic rhinitis enriches the therapeutic means of the allergic rhinitis.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the number of nasal deflection in mice within 10 minutes for each experimental group in the animal behavioral scoring experiment of example 1;
FIG. 2 shows the number of sneezes performed in the mice of each experimental group for 10 minutes in the animal behavioral scoring experiment of example 1;
FIG. 3 shows the number of nasal deflection and sneeze cycles in mice of each experimental group for 10 minutes in the animal behavioral scoring experiment of example 1;
FIG. 4 is the final symptom score for each experimental group of mice in the animal behavioral scoring experiment of example 1;
FIG. 5 is a graph showing the symptom score of each group of mice in the animal behavioral scoring experiment of example 1 over time;
FIG. 6 shows the results of staining the nasal mucosa HE and PAS of mice in each experimental group in the nasal mucosa pathology staining experiment of example 1.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Hepatocyte growth factor (Hepatocyte growth factor, HGF) is a multifunctional cytokine, originally discovered as tissue plasminogen (HGF/SF). It is produced by hepatocytes and other cell types that, in addition to playing a key role in liver regeneration, repair and functional regulation, can also regulate a variety of biological processes through its c-MET receptor activation signaling pathway. For example, hepatocyte growth factor can inhibit neutrophil infiltration by down-regulating adhesion molecules (such as ICAM-1/E-selectin) on endothelial cell surfaces, inhibiting ischemia-related damage in various tissues. HGF directly inhibits eosinophil activation and inhibits eosinophil migration by down-regulating inflammatory mediators in allergic inflammation, thereby exerting an anti-inflammatory effect. HGF also reduces allergen-induced Airway Hyperresponsiveness (AHR) in a mouse model of asthma by inhibiting eosinophil and lymphocyte aggregation in the respiratory tract. HGF also reduces local IL-5 and IL-13 levels in asthmatic mice. HGF can inhibit MCP-1 mediated inflammatory responses in the process of mediating anti-fibrosis. In addition, HGF can increase IL-4 and IL-10 levels and reduce interferon-alpha levels both in vitro and in vivo, thereby restoring cardiac function in myocarditis rats. In addition to lymphocytes, HGF also has inhibitory effects on dendritic cells, and Okunishi et al found that HGF inhibited the production of immunocompetent cytokines such as IL-17, IL-23 and interferon-1, resulting in the attenuation of rheumatoid arthritis, using a mouse model of rheumatoid disease. Experiments prove that the application of the hepatocyte growth factor can effectively improve allergic rhinitis and reduce symptomatic score, inflammation level and serum IgE level of the allergic rhinitis.
In a first aspect, there is provided the use of hepatocyte growth factor as a therapeutic agent in the manufacture of a medicament for the treatment and/or alleviation of allergic rhinitis.
"hepatocyte growth factor" in the present invention includes hepatocyte growth factor protein or precursor substances capable of producing hepatocyte growth factor in a subject, exemplary precursor substances including polynucleotides comprising a polynucleotide encoding hepatocyte growth factor.
The term "hepatocyte growth factor" as used herein includes hepatocyte growth factor, isoforms and species homologs expressed by cells naturally expressed by cells or transfected with hepatocyte growth factor genes. The term also includes hepatocyte growth factor that has been engineered, including but not limited to, mutated, truncated, or fused to other domains.
"Polynucleotide" in the present invention refers to a polymeric form of nucleotides of any length, including ribonucleotides and/or deoxyribonucleotides. Examples of polynucleotides include, but are not limited to, single-, double-or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural or derivatized nucleotide bases. When the polynucleotide encodes a protein or polypeptide, the encoding is optionally encoding a sense strand or an antisense strand. The polynucleotide may be naturally occurring, synthetic, recombinant, or any combination thereof.
In an alternative embodiment, the medicament comprises hepatocyte growth factor protein.
In an alternative embodiment, the agent comprises a polynucleotide encoding a hepatocyte growth factor.
In an alternative embodiment, the agent is a nucleic acid agent comprising DNA or mRNA encoding a hepatocyte growth factor in an amount effective to be expressed.
In alternative embodiments, the nucleic acid drug further comprises a delivery formulation for delivery of the polynucleotide, exemplary delivery formulations including, but not limited to, liposomes or lipid nanoparticles.
In alternative embodiments, the nucleic acid agent further comprises a vector for delivering a polynucleotide, wherein the vector is a vehicle into which a genetic element is operably inserted and which allows expression of the genetic element, such as the production of a protein, RNA or DNA encoded by the genetic element, or replication of the genetic element. Exemplary vectors include, but are not limited to, plasmids, microcircular DNA, phagemids, cosmids, or artificial chromosomes.
In an alternative embodiment, the medicament comprises recombinant cells capable of expressing hepatocyte growth factor.
In an alternative embodiment, the hepatocyte growth factor is a human hepatocyte growth factor. An exemplary amino acid sequence of the human hepatocyte growth factor is shown in SEQ ID NO. 1. An exemplary nucleotide sequence of the human hepatocyte growth factor is shown in SEQ ID NO. 2.
In alternative embodiments, the medicament further comprises pharmaceutically acceptable excipients including, but not limited to, one or more of solvents, solubilizers, co-solvents, emulsifiers, colorants, fillers, tonicity modifiers, stabilizers, glidants, flavoring agents, bacteriostats, suspending agents, fragrances, antioxidants, chelating agents, pH adjusting agents, adsorbents, surfactants, protectants, humectants, absorbents, diluents, release modifiers, hardening agents, hollow capsules, and matrix materials.
In alternative embodiments, the dosage form of the drug may be selected from the group consisting of any pharmaceutically acceptable dosage forms in the art including, but not limited to, injection, nasal preparation, inhalation, spray or oral formulation. The appropriate formulation will depend on the route of administration selected, and can be made by those skilled in the art in accordance with common general knowledge in the art, and appropriate excipients are selected.
In an alternative embodiment, the pharmaceutical dosage form is selected from the group consisting of an injection and a nasal preparation. An exemplary nasal formulation is a nasal drop.
In an alternative embodiment, the medicament further comprises a solvent and a buffer component.
In alternative embodiments, the subject of the medicament comprises a mammal including, but not limited to, a human, pig, cow, horse, monkey, rat, mouse, guinea pig, sheep, or goat. The subject may be a patient with allergic rhinitis, or may be an animal model of allergic rhinitis obtained by artificial modeling. In alternative embodiments, the subject comprises an ovalbumin-sensitized BALB/c mouse allergic rhinitis model.
In an alternative embodiment, when the subject is an ovalbumin-sensitized BALB/c mouse allergic rhinitis model, the drug is an intravenous injection, and the content of HGF in the drug is 1-5 mug/ml, preferably 2 mug/ml.
In an alternative embodiment, when the subject is an ovalbumin-sensitized BALB/c mouse allergic rhinitis model, the medicament is a nose drop, and the content of HGF in the medicament is 1-5 mug/ml, preferably 1 mug/ml.
In alternative embodiments, the method for treating and/or alleviating allergic rhinitis comprises reducing inflammatory cell infiltration of nasal mucosa.
In an alternative embodiment, the inflammatory cells include at least one of eosinophils, neutrophils, basophils, lymphocytes and macrophages.
In alternative embodiments, the method for treating and/or alleviating allergic rhinitis comprises reducing eosinophil and lymphocyte infiltration in the nasal mucosa of the subject.
In alternative embodiments, the method for treating and/or alleviating allergic rhinitis comprises alleviating proliferation of goblet cells of nasal mucosa.
The invention is further illustrated by the following specific examples, however, it should be understood that these examples are for the purpose of illustration only in greater detail and are not to be construed as limiting the invention in any way.
Example 1
Efficacy test:
(1) The purpose of the experiment is as follows: and constructing an allergic rhinitis model, and verifying the effect of HGF on allergic rhinitis mice.
(2) Experimental grouping: group 1 WT-PBS, group 2 AR-PBS, group 3 tail vein injection HGF, group 4 nose drip HGF.
(3) Experimental materials: OVA (ovalbumin) (allergen), al (OH) 3 Suspension (adjuvant).
The molding method comprises the following steps: day 0, 7, 14, group 1 was intraperitoneally injected with 200. Mu.l PBS, and groups 2, 3, 4 were intraperitoneally injected with 200. Mu.l (25. Mu. GOVA, 2mgAL (OH) 3 ) Sensitization. Day 18, 19, 20, group 1, group 2 tail vein injections of PBS 50 μl, group 4 nasal drops of HGF solution 20 μl (concentration 1 μg/ml); day 19, group 3 tail vein injection of 50 μl (2 μg/ml) of HGF solution. Day 21-27, group 1 nasal drops with PBS 20 μl, and groups 2, 3, 4 nasal drops with 20 μl of 100 μg OVA challenge.
(4) The experimental contents are as follows: animal behavioral scoring and nasal mucosa pathology staining.
(4.1) animal behavioural scoring:
scoring purpose: determining whether modeling is successful, and determining the severity of symptoms over time.
Scoring node: day 1, 4, 7 of nasal drip excitation.
Scoring items: scratching nose, sneezing, running nose.
Symptom definition: nose scratching/nose friction: when the mouse scratchs the nose with two front paws, a brief and effective nose friction can be recorded. Sneeze: when the mice were "crunched" or sneezed and were shaking their head, they could be recorded as a valid sneeze.
Runny nose/secretions: nasal secretion distribution was observed and faithfully recorded.
The scoring criteria are shown in the following table:
TABLE 1
Molding success standard: and observing and recording within 10 minutes after the last nasal drip excitation, wherein the total score is more than or equal to 5 minutes, and the molding is successful.
Scoring results: the average score of the AR-PBS group had broken through 5 points on day 24 and increased to 5.7 points on day 27, suggesting successful modeling. The speed of rising of symptom scores can be delayed by using tail vein injection HGF and nose drop HGF to intervene in allergic rhinitis mice in advance. The symptom score of the allergic rhinitis mice can be remarkably reduced by using tail vein injection HGF and nasal drop HGF. (FIG. 1-FIG. 5)
(4.2) pathological staining of nasal mucosa
The purpose is as follows: the inflammatory infiltration condition of nasal mucosa is clear.
The method comprises the following steps: after the day 28 mice were sacrificed, the nasal mucosa of each group was stained for HE and PAS.
Results: as shown in fig. 6, the AR-PBS group nasal mucosa HE staining showed a significant increase in eosinophil infiltration and lymphocyte infiltration, and PAS staining showed significant goblet cell proliferation. The inflammatory cell infiltration of the allergic rhinitis mice can be obviously reduced by using the tail vein injection HGF and the nasal drop HGF, and the goblet cell proliferation can be reduced.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (4)
1. Use of a therapeutic agent in the manufacture of a medicament for the treatment and/or alleviation of allergic rhinitis; the medicament is a nasal preparation, and the therapeutic agent is hepatocyte growth factor protein; the hepatocyte growth factor is a human hepatocyte growth factor;
the methods for treating and/or alleviating allergic rhinitis include reducing inflammatory cell infiltration of nasal mucosa and alleviating goblet cell proliferation of nasal mucosa.
2. The use according to claim 1, wherein the medicament is for use in a mammal.
3. The use of claim 1, wherein the medicament further comprises at least one of a pharmaceutically acceptable adjuvant, carrier, and delivery formulation.
4. The use according to claim 1, wherein the inflammatory cells comprise eosinophils and lymphocytes.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2004203855A (en) * | 2002-06-24 | 2004-07-22 | Akira Awaya | Prophylactic and therapeutic method for allergic rhinitis/conjunctivitis, skin allergy and atopic dermatitis |
| JP2006298775A (en) * | 2005-04-15 | 2006-11-02 | Dainippon Sumitomo Pharma Co Ltd | Selective th2 immune reaction inhibitor |
| CN101925584A (en) * | 2007-11-22 | 2010-12-22 | 阿斯利康(瑞典)有限公司 | Pyrimidine Derivatives for the Treatment of Asthma, COPD, Allergic Rhinitis, Allergic Conjunctivitis, Atopic Dermatitis, Cancer, Hepatitis B, Hepatitis C, HIV, HPV, Bacterial Infections and Skin Diseases |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004203855A (en) * | 2002-06-24 | 2004-07-22 | Akira Awaya | Prophylactic and therapeutic method for allergic rhinitis/conjunctivitis, skin allergy and atopic dermatitis |
| JP2006298775A (en) * | 2005-04-15 | 2006-11-02 | Dainippon Sumitomo Pharma Co Ltd | Selective th2 immune reaction inhibitor |
| CN101925584A (en) * | 2007-11-22 | 2010-12-22 | 阿斯利康(瑞典)有限公司 | Pyrimidine Derivatives for the Treatment of Asthma, COPD, Allergic Rhinitis, Allergic Conjunctivitis, Atopic Dermatitis, Cancer, Hepatitis B, Hepatitis C, HIV, HPV, Bacterial Infections and Skin Diseases |
Non-Patent Citations (2)
| Title |
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| Anti-Allergic Inflammatory Effects of Hepatocyte Growth Factor;Wataru Ito等;《Int Arch Allergy Immunol》;第146卷;第82-87页 * |
| The role of hepatocyte growth Factor/c-Met in chronic rhinosinusitis with nasal polyps;Douglas D. Reh, M.D.等;《Am J Rhinol Allergy》;第24卷(第4期);第1-13页 * |
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