Application of FGF21 inhibitor or FGF21 antagonist in preparation of medicine for treating obesity-induced asthma or airway hyperresponse

Abstract

The invention discloses an application of an FGF21 (fibroblast growth factor 21) inhibitor or an FGF21 antagonist in preparation of a medicine for treating obesity-induced asthma or airway hyperreaction. The invention provides a gene or protein FGF21 related to obesity-induced airway hyperresponsiveness, and the FGF21 can be used as a new target of obesity-asthma airway hyperresponsiveness to develop related novel drugs, so that a theoretical basis and a new drug target are provided for research and development of drugs for obesity-asthma.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically, to the use of an FGF21 inhibitor or an FGF21 antagonist in the preparation of a drug for treating obesity-induced airway hyperreactivity or asthma. Background Art

[0002] Obesity is a chronic metabolic disease characterized by excessive fat accumulation, which can lead to chronic inflammation of adipose tissue and the whole body, and promote the occurrence of insulin resistance, which can directly lead to or promote the occurrence and development of various diseases such as diabetes, tumors, and asthma. Among them, asthma is a heterogeneous disease, including multiple clinical phenotypes. Obesity is an independent risk factor for the occurrence or aggravation of asthma. On the contrary, weight loss can significantly improve asthma symptoms and reduce the frequency of acute attacks. Obese asthma is a common and special type of asthma in clinical practice. Unlike other types of asthma, obese asthma is insensitive to inhaled glucocorticoid treatment and has poor clinical outcomes. As the obese population increases, the number of patients with obese asthma will also increase, and related clinical problems will become increasingly prominent.

[0003] One of the important pathological factors that induces airway hyperresponsiveness and aggravates asthma is that obesity can reshape the body's immune state. The first is the change of immune cells in the adipose tissue under the obese body, which is manifested as an increase in Th1 and Th17, a decrease in Treg and Th2, ILC2 cell dysfunction, a decrease in M2 macrophages, and an increase in neutrophils. The corresponding immune-related factors also undergo pathological changes, including increased secretion of pro-inflammatory factors IFN-γ, IL-17, IL-6, IL-1β, TNF-α, and IL-33, and decreased secretion of anti-inflammatory factors IL-4 and IL-10. It has been found that a variety of key cytokines are involved in regulating the immune state of obese bodies, including non-fat factors and fat factors leptin and adiponectin. Studies have found that fibroblast growth factor FGF21 is encoded by the FGF21 gene and is an important cytokine that maintains the body's metabolic homeostasis. It is mainly synthesized by the liver and can be released into the blood as an endocrine factor. It has important application potential in metabolic diseases such as obesity, diabetes, and fatty liver. However, there are no reports on whether FGF21 is involved in regulating the immune status of obese individuals and whether it plays an important role in obesity-induced airway hyperresponsiveness or asthma. Summary of the invention

[0004] An object of the present invention is to solve at least the above problems and to provide at least the advantages which will be described hereinafter.

[0005] In order to achieve these objectives and other advantages according to the present invention, there is provided a use of an FGF21 inhibitor or an FGF21 antagonist in the preparation of a medicament for treating obesity-induced asthma.

[0006] The present invention provides an application of an FGF21 inhibitor or an FGF21 antagonist in preparing a drug for treating obesity-induced airway hyperresponsiveness.

[0007] Preferably, in the application, the FGF21 inhibitor or FGF21 antagonist is used as an active ingredient in a single component drug or a combination drug.

[0008] Preferably, the use, the single component drug or the combination drug further comprises a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0009] Preferably, the use, the single component drug or the combined drug is prepared into a pharmaceutically acceptable dosage form.

[0010] Preferably, in the application, the dosage form includes pills, tablets, powders, capsules, granules, powders, pellets, drops, sprays, injections, suspensions, ointments, gels, and suppositories.

[0011] The present invention has at least the following beneficial effects:

[0012] The present invention provides a gene or protein FGF21 related to obesity-induced airway hyperresponsiveness or asthma. FGF21 can be used as a new target for obese asthma or airway hyperresponsiveness to develop related new drugs, providing a theoretical basis and a new drug target for the drug development of obese asthma.

[0013] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is a structural diagram comparing various indicators of mice in the normal group and the obese group in Example 1 of the present invention, wherein: Figure 1 A is the statistical analysis result of the body weight of mice in the normal group and the obese group; Figure 1 B is the statistical analysis result of blood glucose of mice in normal group and obese group; Figure 1 C is the statistical analysis result of FGF21 content in the serum of mice in the normal group and the obese group; Figure 1 D is the statistical analysis result of FGF21 content in bronchoalveolar lavage fluid of mice in normal group and obese group;

[0015] Figure 2 This is a comparison chart of the non-invasive lung function test results of mice in the normal diet control group (Lean), the high-fat diet control group (Obese), and the high-fat diet + recombinant protein FGF21 group (Obese+FGF21) in Example 2 of the present invention;

[0016] Figure 3This is a comparison chart of the invasive lung function test results of mice in the normal diet control antibody group (Lean+IgG), the normal diet FGF21 antibody group (Lean+Anti-FGF21), the high-fat diet control antibody group (Obese+IgG), and the high-fat diet FGF21 antibody group (Obese+Anti-FGF21) in Example 3 of the present invention. DETAILED DESCRIPTION

[0017] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments so that those skilled in the art can implement the invention with reference to the description.

[0018] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0019] It should be noted that the experimental methods described in the following embodiments are conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0020] Fibroblast growth factor FGF21 is encoded by the FGF21 gene. It is an important cytokine that maintains metabolic homeostasis. It is mainly synthesized by the liver and can be released into the blood to act as an endocrine factor. It has important application potential in metabolic diseases such as obesity, diabetes, and fatty liver. There are no reports on whether FGF21 is involved in regulating the immune state of obese bodies and whether it plays an important role in obesity-induced airway hyperresponsiveness or asthma. The study found that FGF21 has a promoting effect on obesity-induced airway hyperresponsiveness. Therefore, relevant research on the technology of FGF21 in the preparation of drugs for the treatment of obesity-induced airway hyperresponsiveness asthma has been launched.

[0021] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention.

[0022] Example 1

[0023] FGF21 levels are significantly increased in serum and bronchoalveolar lavage fluid of high-fat diet-induced obese mice

[0024] Ten 6-week-old male C57BL / 6J mice were selected and divided into two groups, namely the normal group (lean) and the obese group (Obese). The mice were fed with a normal diet (CD, fat 10% kcal, carbohydrate 70% kcal, protein 20% kcal) and a high-fat diet (HFD, fat 60% kcal, carbohydrate 20% kcal, protein 20% kcal) for 16 weeks, respectively. The body weight of the mice was measured every 4 weeks, and the fasting blood glucose (FBG) of the mice was measured once every 4 weeks. The last measurement result was recorded as follows: Figure 1 A- Figure 1 As shown in B, Figure 1 A and Figure 1 B shows that the body weight and blood glucose of the obese group were significantly higher than those of the normal group mice (data are shown in the form of mean ± SEM).

[0025] After the two groups of mice were fed for 16 weeks, they were anesthetized with pentobarbital, blood was collected after bronchoalveolar lavage, and then they were killed by cervical dislocation. The supernatant of bronchoalveolar lavage fluid (BALF) and serum were collected, and the FGF21 content was determined by ELISA (Mouse FGF21 ELISA Kit, Sangon Biotech). Figure 1 As shown in CD, the levels of FGF21 in the serum and bronchoalveolar lavage fluid of the obese group of mice were significantly higher than those of the normal group of mice (data are shown as mean ± SEM).

[0026] Example 2

[0027] Recombinant protein FGF21 exacerbates airway hyperresponsiveness in obese mice

[0028] Six-week-old male C57BL / 6J mice were selected and divided into three groups, namely, normal diet control group (Lean), high-fat diet control group (Obese), high-fat diet + recombinant protein FGF21 group (Obese+FGF21), 5 mice in each group, the normal diet control group (Lean) was given a normal diet (CD, fat 10% kcal, carbohydrate 70% kcal, protein 20% kcal), the high-fat diet control group (Obese) and high-fat diet + recombinant protein FGF21 group (Obese+FGF21) were given a high-fat diet (HFD, fat 60% kcal, carbohydrate 20% kcal, protein 20% kcal), all fed for 16 weeks, and non-invasive lung function test was performed at the 22nd week of age ( FinePointe, DSI), 24h before the test, the normal diet control group (Lean) and the high-fat diet control group (Obese) were injected with normal saline (1.5mg / kg), and the high-fat diet + recombinant protein FGF21 group (Obese+FGF21) was injected with recombinant protein FGF21 (1.5mg / kg); acetylcholine was used in the test at concentrations of 0, 12.5, 25, and 50mg / mL, with an adaptation time of 5min, atomization time of 1min, reaction time of 5min, and recovery time of 2min. The sRaw value within the reaction time range was recorded. The results are shown in Figure 2 As shown, compared with mice in the normal diet control group (Lean), mice in the high-fat diet control group (Obese) had pathological airway hyperresponsiveness, and the airway resistance values ​​were significantly higher than those of mice on a normal diet. The airway hyperresponsiveness of mice in the high-fat diet + recombinant protein FGF21 group (Obese+FGF21) was significantly higher than that in the high-fat diet control group (Obese), that is, recombinant protein FGF21 can aggravate the airway hyperresponsiveness of obese mice (data are shown as mean ± SEM).

[0029] Example 3

[0030] FGF21 antibody significantly alleviates airway hyperresponsiveness in obese mice

[0031] Six-week-old male C57BL / 6J mice were selected and divided into four groups, namely, normal diet control antibody group (Lean+IgG), normal diet FGF21 antibody group (Lean+Anti-FGF21), high-fat diet control antibody group (Obese+IgG), and high-fat diet FGF21 antibody group (Obese+Anti-FGF21), with 5 mice in each group. The normal diet control antibody group (Lean+IgG) and the normal diet FGF21 antibody group (Lean+Anti-FGF21) were given a normal diet (CD, fat 10% kcal, carbohydrate 70% kcal, protein 20% kcal); the high-fat diet control antibody group (Obese+IgG) and the high-fat diet FGF21 antibody group (Obese+Anti-FGF21) were given a high-fat diet (HFD, fat 60% kcal, carbohydrate 20% kcal, protein The mice were fed with a normal diet control antibody group (Lean+IgG) and a high-fat diet control antibody group (Obese+IgG) and were injected with control immunoglobulin G (IgG); the mice were fed with a normal diet FGF21 antibody group (Lean+Anti-FGF21) and a high-fat diet FGF21 antibody group (Obese+Anti-FGF21) and were injected with Anti-FGF21 (FGF21 antagonist). The injection dose was 10 μg / mouse, once every 4 days, for a total of 3 injections. Then, invasive pulmonary function tests were performed (AniRes2005 animal pulmonary function analysis system, Bellambo). Methacholine was used in the test at concentrations of 0, 0.2, 0.4, and 0.8 mg / mouse). The adaptation time was 5 min, the reaction time was 5 min, and the recovery time was 2 min. The RL value within the reaction time range was recorded.

[0032] The results are as follows Figure 3 As shown, the airway responsiveness of mice in the normal diet FGF21 antibody group (Lean+Anti-FGF21) did not show significant changes compared with the normal diet control antibody group (Lean+IgG), while the airway responsiveness of mice in the high-fat diet FGF21 antibody group (Obese+Anti-FGF21) was significantly decreased compared with the high-fat diet control antibody group (Obese+IgG), especially at high concentrations of methacholine (0.4 mg / mouse, 0.8 mg / mouse). This shows that FGF21 antagonists can significantly alleviate airway hyperresponsiveness in obese mice (data are shown as mean ± SEM).

[0033] FGF21 has a promoting effect on obesity-induced airway hyperresponsiveness. Pharmacological FGF21 antagonists can alleviate obesity-induced airway hyperresponsiveness. Specifically, the FGF21 levels in the serum and bronchoalveolar lavage fluid of obese mice induced by a high-fat diet were significantly higher than those of mice fed a normal diet ( Figure 1 C-1D); In the lung function test experiment, compared with the lean mice on a normal diet, the obese mice induced by a high-fat diet had pathological airway hyperresponsiveness, and the injection of recombinant protein FGF21 exacerbated the airway hyperresponsiveness of obese mice ( Figure 2 ); injection of the antibody Anti-FGF21 significantly alleviated the airway hyperresponsiveness of obese mice ( Figure 3 ), it can be seen that FGF21 can be used as a new target for obese asthma or airway hyperresponsiveness to develop related new drugs, providing a theoretical basis and new drug targets for the development of drugs for obese asthma.

[0034] The number of devices and processing scales described here are used to simplify the description of the present invention. Applications, modifications and variations of the present invention will be obvious to those skilled in the art.

[0035] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes, and they can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to the specific details and the illustrations shown and described herein.

Claims

1. Use of FGF21 inhibitors or FGF21 antagonists in the preparation of drugs for treating obesity-induced asthma.

2. Use of FGF21 inhibitors or FGF21 antagonists in the preparation of drugs for treating obesity-induced airway hyperresponsiveness.

3. The use according to claims 1 to 2, characterized in that: The FGF21 inhibitor or FGF21 antagonist is used as a single component drug or an active ingredient in a combination drug.

4. The use according to claim 3, characterized in that The single component drug or the combined drug further includes a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. The use according to claim 4, characterized in that The single component drug or the combined drug is prepared into a pharmaceutically acceptable dosage form.

6. The use according to claim 5, characterized in that The dosage forms include pills, tablets, powders, capsules, granules, powders, pellets, drops, sprays, injections, suspensions, ointments, gels, and suppositories.

Images