Drug for preventing or treating fibrotic diseases

Abstract

The present invention provides use of VEGF-C156S in the preparation of a drug for fibrotic diseases.

Description

A drug used to prevent or treat fibrosis. Technical Field

[0001] This invention relates to the field of prevention and / or treatment of fibrotic diseases, and more specifically to the use of VEGF-C156S in the prevention and / or treatment of fibrotic diseases. Background Technology

[0002] Pulmonary fibrosis is the end-stage clinical manifestation of many interstitial lung diseases with different etiologies. It is characterized by persistent alveolar damage, fibroblast proliferation, and massive extracellular matrix (ECM) deposition, which leads to varying degrees of inflammation and fibrosis in the alveoli and interstitium, resulting in lung structural destruction and respiratory failure. Therefore, it is also known as interstitial lung disease.

[0003] Idiopathic pulmonary fibrosis (IPF) is the most common and severe chronic inflammatory interstitial lung disease of unknown etiology. Clinically, it presents as progressive dyspnea accompanied by a persistent dry cough. The disease is usually progressive, with a median survival of approximately 2.8 years and a 5-year survival rate of less than 50%. Most patients die from respiratory failure and secondary lung infections. IPF has been reported worldwide, and its incidence has been steadily increasing in recent years without significant geographical or racial differences. Patients are mostly middle-aged and elderly, typically developing the disease between 50 and 70 years of age, and it is rare in children. Given the large number of clinical cases, the prevalence and incidence of IPF are difficult to estimate; it is estimated to occur in 15-250 out of 100,000 people, with approximately 34,000 new cases annually depending on country, age, and sex. Currently, lung transplantation is the only treatment that can prolong the survival of patients with pulmonary fibrosis (IPF). The "Chinese Expert Consensus on the Diagnosis and Treatment of IPF" recommends pirfenidone, nintedanib, antacids, and N-acetylcysteine ​​as primary drug treatments for IPF. Among these, only pirfenidone and nintedanib are approved as effective treatments for IPF. While these drugs can slow the decline in lung function, they cannot reverse disease progression, and a significant proportion of patients have poor treatment responses. Furthermore, their specific pharmacological mechanisms are not fully understood. Therefore, elucidating the mechanisms of pulmonary fibrosis development, exploring new potential drug targets, and developing effective, relatively safe, and affordable drugs for pulmonary fibrosis are of significant social and medical importance. Summary of the Invention

[0004] The purpose of this invention is to provide a new drug that can effectively prevent and / or treat fibrotic diseases.

[0005] In a first aspect, the present invention provides the use of VEGF-C156S in the preparation of a pharmaceutical composition for the prevention and / or treatment of fibrotic diseases in a subject.

[0006] In another preferred embodiment, the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, cardiac fibrosis, renal fibrosis, pancreatic fibrosis, skin fibrosis, intestinal fibrosis, ocular fibrosis, esophageal fibrosis, or combinations thereof.

[0007] In another preferred embodiment, the prevention and / or treatment of fibrotic diseases includes one or more features selected from the group consisting of:

[0008] (1) Reduce extracellular matrix proliferation and deposition;

[0009] (2) Improve inflammation (reduce inflammatory factors such as IL-1β, IL-6, and CCL2);

[0010] (3) Improve the molecular levels of fibrosis-related indicators (such as reducing hydroxyproline, α-SMA, COL-1 and / or Fibronectin levels);

[0011] (4) Reduce tissue damage (protect the function of tissues and organs).

[0012] In another preferred embodiment, the fibrotic disease is pulmonary fibrosis.

[0013] In another preferred embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.

[0014] In another preferred embodiment, the prevention and / or treatment of pulmonary fibrosis includes one or more features selected from the group consisting of:

[0015] Improve alveolar structure;

[0016] Reduces the proliferation of mesenchymal cells in lung tissue;

[0017] Reduce total cell count and LDH content in bronchoalveolar lavage fluid;

[0018] Improves inflammation (reduces inflammatory factors such as IL-1β, IL-6, and CCL2);

[0019] Reduce extracellular matrix proliferation and deposition;

[0020] Reduce hydroxyproline content;

[0021] Improve the molecular levels of fibrosis-related markers (such as reducing hydroxyproline, α-SMA, COL-1, and / or Fibronectin levels); and / or

[0022] Reduce lung damage and improve lung function.

[0023] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of liquid formulations (such as solutions, emulsions, suspensions) and solid formulations (such as lyophilized formulations).

[0024] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: injections (such as solutions or powders for injection), oral preparations (such as capsules or tablets), microspheres or microcapsules for sustained release, liposomes, nanoparticles, and implants.

[0025] In another preferred embodiment, VEGF-C156S is the sole active ingredient in the pharmaceutical composition.

[0026] In another preferred embodiment, the subject is a mammal.

[0027] In another preferred embodiment, the subject is a human, rat, or mouse.

[0028] In a second aspect, the present invention provides a method for preventing and / or treating fibrotic diseases in a subject, comprising the steps of administering VEGF-C156S or a formulation thereof to a subject in need, thereby preventing and / or treating fibrotic diseases.

[0029] In another preferred embodiment, the subject is a mammal.

[0030] In another preferred embodiment, the subject is a human, rat, or mouse.

[0031] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0032] Figure 1 shows the effects of VEGF-C156S intervention on lung injury and inflammatory markers in mice;

[0033] Figure 2 shows the effects of VEGF-C156S intervention on pulmonary fibrosis markers in mice;

[0034] Figure 3 shows the effects of VEGF-C156S intervention on lung function indicators in mice. Detailed Implementation

[0035] Through extensive and in-depth research, including numerous screenings and tests, the inventors have developed a drug for the prevention and treatment of fibrotic diseases. The inventors unexpectedly discovered for the first time that the use of VEGF-C156S can significantly protect subjects from tissue damage and fibrosis, thus providing the use of VEGF-C156S in the prevention and treatment of fibrotic diseases. This invention was completed based on this discovery.

[0036] the term

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0038] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0039] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0040] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0041] fibrosis

[0042] Fibrosis is a group of pathological conditions affecting multiple organ systems throughout the body. It is characterized by the gradual replacement of normal organ tissues with fibrous connective tissue, leading to tissue structural damage, functional decline, and even organ failure. This process is usually caused by a dysregulation of the repair response following chronic inflammation or tissue injury. Fibrosis typically begins with an inflammatory response after tissue damage, subsequently activating fibroblasts to transform into myofibroblasts. These cells produce large amounts of collagen and other extracellular matrix (ECM) components, ultimately leading to tissue hardening and loss of function.

[0043] Common fibrotic diseases include (but are not limited to): pulmonary fibrosis, liver fibrosis, cardiac fibrosis, renal fibrosis, pancreatic fibrosis, skin fibrosis, intestinal fibrosis, ocular fibrosis, esophageal fibrosis, or combinations thereof.

[0044] In this invention, fibrotic diseases include pulmonary fibrosis. The main pathological features of pulmonary fibrosis include mesenchymal cell proliferation in lung tissue, extracellular matrix hyperplasia and deposition, and lung parenchymal remodeling. Currently, the main treatments for pulmonary fibrosis include anti-inflammatory, anti-oxidative, anti-fibroblast proliferation and collagen deposition measures, and lung transplantation.

[0045] In this invention, the term "subject" refers to a mammal, including but not limited to rats, mice, non-human primates, humans, dogs, cats, horses, cattle, sheep, pigs, and goats. Humans or mice are preferred.

[0046] The term "prevention" in this invention refers to preventing or reducing the occurrence of fibrosis after use in the presence of possible fibrotic factors. The term "treatment" in this invention refers to reducing the degree of fibrosis, curing fibrosis to normalize it, or slowing the progression of fibrosis.

[0047] VEGF-C156S

[0048] VEGF-C is a member of the VEGF family of vascular endothelial growth factors. VEGF signaling occurs via the tyrosine kinase receptor VEGFR, which is expressed in the endothelial cells of blood and lymphatic vessels. The receptor VEGFR-3, which VEGF-C primarily targets, has been shown to be a key regulator of lymphangiogenesis. Although VEGF-C preferentially promotes lymphatic vessel growth by activating VEGFR-3, high levels of these growth factors have been shown to induce adverse vascular changes, such as vascular enlargement, tortuosity, and increased vascular permeability, ultimately leading to tissue edema.

[0049] To minimize these adverse side effects, the point mutation form of VEGF-C, VEGF-C156S, has been investigated. VEGF-C156S is a selective agonist targeting only VEGFR-3, capable of inducing lymphangiogenesis without affecting angiogenesis, and can be more specifically involved in the treatment of pulmonary fibrosis. Currently, there are no reported studies on the use of VEGF-C156S in fibrosis-related fields.

[0050] This invention unexpectedly reveals for the first time that VEGF-C156S has a very significant therapeutic effect on fibrotic diseases. For example, in a pulmonary fibrosis model, administration of VEGF-C156S significantly improved alveolar structure, reduced mesenchymal cell proliferation in lung tissue, decreased total cell count and LDH content in bronchoalveolar lavage fluid, significantly reduced IL-1β, IL-6, and CCL2 levels, improved inflammation, reduced extracellular matrix proliferation and deposition, reduced hydroxyproline content, and reduced α-SMA, COL-1, and Fibronectin levels. This reduces lung damage at both the molecular and tissue levels, improves pulmonary fibrosis, and enhances lung function. Therefore, VEGF-C156S can effectively prevent or treat fibrotic diseases.

[0051] One possible reason is (but not limiting the invention) that VEGF-C156S repairs lymphatic vessel damage and dysfunction by selectively inducing lymphatic vessel regeneration, thereby further improving fluid balance at the lesion site, reducing inflammation, and promoting tissue repair.

[0052] The amino acid sequence of VEGF-C156S is as follows (SEQ ID NO:1):

[0053] Pharmaceutical Composition

[0054] In this invention, a pharmaceutical composition containing VEGF-C156S of this invention as an active ingredient is also provided.

[0055] The pharmaceutical compositions of the present invention contain a safe and effective amount (e.g., 0.001-99 wt%, preferably 0.01-90 wt%, more preferably 0.1-80 wt%) of the active ingredient of the present invention and a pharmaceutically acceptable carrier or excipient. Such carriers include (but are not limited to): saline, buffer solutions, glucose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical formulation should be matched to the route of administration. The pharmaceutical compositions of the present invention can be formulated into injectable forms, for example, prepared using conventional methods with physiological saline or aqueous solutions containing glucose and other excipients. Pharmaceutical compositions such as injections and solutions are preferably manufactured under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount, for example, about 10 micrograms / kg body weight to about 50 mg / kg body weight per day. Furthermore, the polypeptides of the present invention can be used with other therapeutic agents. The fusion protein or its immunoconjugate can be formulated with pharmaceutically acceptable excipients to achieve more stable therapeutic effects. These formulations ensure the structural integrity of the amino acid core sequence of the fusion protein of the present invention while protecting the multifunctional groups of the protein from degradation (including but not limited to aggregation, deamination, or oxidation). The formulation can be in various forms. Generally, liquid formulations can be stably stored for at least one year at 2℃-8℃, and lyophilized formulations can remain stable for at least six months at 30℃. The formulation can be a commonly used pharmaceutical preparation such as a suspension, injection, or lyophilized form, with injection or lyophilized formulations being preferred.

[0056] For the pharmaceutical compositions of the present invention (such as aqueous injections or lyophilized formulations), pharmaceutically acceptable excipients include one or a combination of surfactants, solution stabilizers, isotonic modifiers, and buffers. Surfactants include nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters (Tween 20 or 80); poloxamer (such as poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; tetradecyl, linoleic, or octadecyl sarcosine; Pluronics; MONAQUAT™, etc., added in an amount that minimizes the tendency of protein granulation. Solution stabilizers can be sugars, including reducing and non-reducing sugars; amino acids, including monosodium glutamate or histidine; alcohols, including one or a combination of triols, higher sugar alcohols, propylene glycol, and polyethylene glycol. The amount of solution stabilizer added should be such that the final formulation is considered by a person skilled in the art to remain stable for a stable period of time. Isotonic modifiers can be one of sodium chloride and mannitol. Buffers can be one of TRIS, histidine buffer, and phosphate buffer.

[0057] When using the pharmaceutical composition, a safe and effective amount of the active ingredient of the present invention is administered to mammals, wherein the safe and effective amount is generally at least about 50 micrograms per kilogram of body weight, and in most cases does not exceed about 100 milligrams per kilogram of body weight, preferably between about 100 micrograms per kilogram of body weight and about 50 milligrams per kilogram of body weight. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise. Typically, the total dosage should not exceed a certain range, for example, the intravenous dose is 10 to 3000 mg / day / 50 kg, preferably 100 to 1000 mg / day / 50 kg.

[0058] The active ingredients of this invention and pharmaceutical preparations containing them can be used as anti-fibrotic drugs for the prevention or treatment of fibrotic diseases.

[0059] The active ingredients and pharmaceutical preparations of the present invention can also be administered in combination with other drugs, including but not limited to: 1. antifibrotic drugs such as pirfenidone and nintedanib; glucocorticoids such as prednisone; immunosuppressants such as azathioprine and cyclophosphamide; and antioxidants such as N-acetylcysteine ​​(NAC).

[0060] The main advantages of this invention include:

[0061] This invention provides a novel drug for the prevention or treatment of fibrotic diseases.

[0062] Experiments have shown that VEGF-C156S has significant and excellent therapeutic effects on fibrotic diseases, and is expected to provide a new solution for the treatment of fibrotic diseases.

[0063] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0064] Example 1

[0065] VEGF-C156S intervention slowed bleomycin-induced pulmonary fibrosis in mice.

[0066] Animal model preparation: Male C57BL / 6J mice, aged 8-10 weeks (n=6 in the saline control group, n=8 in the model group, and n=6 in the bleomycin model group + VEGF-C156S administration group), were anesthetized by intraperitoneal injection of 10% sodium pentobarbital. Bleomycin was injected into the trachea to establish the model. Mice that received the same volume of saline via airway injection served as controls. Five days after bleomycin administration, mice were given intravenous intervention with 125 μg / kg VEGF-C156S once daily (administration group). The normal control group and model group received the same volume of saline injection. The degree of pulmonary fibrosis in each mouse was analyzed 14 days after administration.

[0067] As shown in Figure 1 (A and B), H&E staining of pathological sections revealed that, compared to the normal control group, the alveolar structure of mice in the BLM model group was disrupted and the pulmonary interstitium was thickened. The VEGF-C156S administration group significantly improved alveolar structure and reduced the proliferation of mesenchymal cells in the lung tissue. Compared to the normal control group, the H&E index of mice in the BLM model group was significantly increased, while the H&E index of mice in the VEGF-C156S administration group was significantly reduced, alleviating lung damage. Compared with nintedanib, a positive drug for pulmonary fibrosis treatment reported in other literature, nintedanib reduced the H&E index in the lungs of pulmonary fibrosis model mice by approximately 27.5%, while VEGF-C156S administration reduced the H&E index in the lungs of pulmonary fibrosis model mice by approximately 33.3%. VEGF-C156S administration showed a better effect in alleviating lung structural damage in pulmonary fibrosis model mice.

[0068] As shown in Figures 1C and D, the total cell count and LDH content in the bronchoalveolar lavage fluid (BALAF) of mice in the BLM model group were significantly increased compared to the normal control group. The VEGF-C156S administration group significantly reduced the total cell count and LDH content in BLAF, alleviating lung injury. Compared with nintedanib, a positive drug for pulmonary fibrosis treatment reported in the literature, nintedanib reduced the total cell count in BLAF of pulmonary fibrosis model mice by approximately 25.0%, but did not significantly reduce the LDH content. VEGF-C156S administration reduced the total cell count in BLAF of pulmonary fibrosis model mice by approximately 55.5%, and reduced the LDH content by approximately 55%. Therefore, VEGF-C156S administration showed better results in reducing the total cell count and LDH content in BLAF of pulmonary fibrosis model mice.

[0069] As shown in Figure 1E, the expression results of inflammation-related genes revealed that, compared with the normal control group, the levels of IL-1β, IL-6, and CCL2 in the lung tissue of mice in the BLM model group were significantly increased. The VEGF-C156S administration group significantly reduced the levels of IL-1β, IL-6, and CCL2, alleviating lung injury and improving inflammation. Compared with nintedanib, a positive drug for treating pulmonary fibrosis reported in the literature, nintedanib reduced IL-1β by approximately 25.0% and IL-6 by approximately 50.0% in pulmonary fibrosis model mice. VEGF-C156S administration reduced IL-1β by approximately 80.0% and IL-6 by approximately 55.0% in pulmonary fibrosis model mice. VEGF-C156S administration showed a better reduction in the transcriptional levels of inflammation-related genes in pulmonary fibrosis model mice.

[0070] In summary, as shown in Figure 1, the H&E staining, total cell count in bronchoalveolar lavage fluid, LDH content, and expression of inflammation-related genes indicate that, compared with the model group mice, mice treated with VEGF-C156S exhibited less lung damage and improved inflammation. Furthermore, VEGF-C156S showed superior anti-inflammatory effects compared to the marketed pulmonary fibrosis-positive drug nintedanib.

[0071] Masson staining of pathological sections A and B in Figure 2 shows that, compared with the normal control group, the BLM model mice exhibited extracellular matrix proliferation and deposition. The VEGF-C156S administration group significantly reduced extracellular matrix proliferation and deposition, alleviating pulmonary fibrosis. Compared with the normal control group, the fibrosis score of the BLM model mice was significantly increased, while the VEGF-C156S administration group showed a significant decrease in fibrosis score, alleviating pulmonary fibrosis. Compared with nintedanib, a positive drug for treating pulmonary fibrosis reported in the literature, nintedanib can reduce the pulmonary fibrosis score in pulmonary fibrosis model mice by approximately 8.5%, while VEGF-C156S administration can reduce the pulmonary fibrosis score in pulmonary fibrosis model mice by approximately 16.6%. VEGF-C156S administration has a better effect in alleviating extracellular matrix deposition in the lungs of pulmonary fibrosis model mice.

[0072] As shown in Figure 2C, the hydroxyproline content in the lung tissue of mice in the BLM model group was significantly increased compared to the normal control group. The VEGF-C156S administration group significantly reduced the hydroxyproline content in mice, alleviating pulmonary fibrosis. Compared with nintedanib, a positive drug for treating pulmonary fibrosis reported in the literature, nintedanib can reduce the hydroxyproline content in the lungs of pulmonary fibrosis model mice by approximately 25%, while VEGF-C156S administration can reduce the pulmonary fibrosis score in pulmonary fibrosis model mice by approximately 33.3%. VEGF-C156S administration has a better effect in alleviating hydroxyproline deposition in the lungs of pulmonary fibrosis model mice.

[0073] As shown in Figure 2D, the transcription results of fibrosis-related genes showed that, compared with the normal control group, the levels of α-SMA, COL-1, and Fibronectin in the lung tissue of mice in the BLM model group were significantly increased, while the VEGF-C156S administration group could significantly reduce the levels of α-SMA, COL-1, and Fibronectin in mice and alleviate pulmonary fibrosis. Compared with nintedanib, a positive drug for pulmonary fibrosis treatment reported in the literature, nintedanib reduced α-SMA by approximately 45.0%, COL-1 by approximately 50.0%, and Fibronectin by approximately 50.0% in pulmonary fibrosis model mice. VEGF-C156S administration reduced α-SMA by approximately 50.0%, COL-1 by approximately 55.0%, and Fibronectin by approximately 50.0% in pulmonary fibrosis model mice. VEGF-C156S administration showed better reduction in the transcriptional levels of fibrosis-related genes in pulmonary fibrosis model mice.

[0074] In summary, Figure 2 shows that Masson staining, hydroxyproline levels, and transcription results of fibrosis-related genes indicate that, compared to the model group mice, mice treated with VEGF-C156S exhibited less lung injury and improved pulmonary fibrosis. Furthermore, VEGF-C156S showed better efficacy in improving lung injury than the marketed pulmonary fibrosis-positive drug nintedanib.

[0075] As shown in Figures 3A, B, and C, the results of forced vital capacity (FVC), forced expiratory volume in 100 milliseconds (FEV100), and inspiratory volume (IC) in mice showed that, compared with the normal control group, the FVC, FEV100, and IC volumes of mice in the BLM model group were significantly decreased, while the VEGF-C156S administration group significantly increased the FVC, FEV100, and IC volumes of mice. Compared with nintedanib, a positive drug for treating pulmonary fibrosis reported in the literature, nintedanib increased FVC by approximately 20.0% and FEV100 by approximately 25.0% in mice with pulmonary fibrosis, while VEGF-C156S administration increased FVC by approximately 28.5% and FEV100 by approximately 27.5% in mice with pulmonary fibrosis. VEGF-C156S administration demonstrated a better ability to restore lung function in mice with pulmonary fibrosis.

[0076] As shown in Figures 3D and E, the lung resistance (IR) and dynamic compliance (Cdyn) results indicate that, compared with the normal control group, the IR of mice in the BLM model group was significantly increased, while the IR of mice in the VEGF-C156S administration group was decreased. Compared with the normal control group, the Cdyn of mice in the BLM model group was significantly decreased, while the Cdyn of mice in the VEGF-C156S administration group was significantly increased. Compared with nintedanib, a positive drug for treating pulmonary fibrosis reported in the literature, nintedanib can reduce the IR of pulmonary fibrosis model mice by about 5.0% and increase the Cdyn of pulmonary fibrosis model mice by about 25.0%. VEGF-C156S administration can reduce the IR of pulmonary fibrosis model mice by about 10.0% and increase the Cdyn of pulmonary fibrosis model mice by about 40%. VEGF-C156S administration has a better ability to restore lung function in pulmonary fibrosis model mice.

[0077] In summary, the results in Figure 3 regarding inspiratory volume (IC), forced vital capacity (FVC), forced expiratory volume per 100 ms (FEV100), lung resistance (IR), and dynamic compliance (Cdyn) show that mice treated with VEGF-C156S exhibited less lung function impairment compared to the model group. Furthermore, VEGF-C156S demonstrated a superior effect in improving lung function compared to the marketed pulmonary fibrosis-positive drug nintedanib.

[0078] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of VEGF-C156S in the preparation of pharmaceutical compositions for the prevention and / or treatment of fibrotic diseases in subjects.

2. The use according to claim 1, wherein, The fibrotic diseases are selected from the following group: pulmonary fibrosis, liver fibrosis, cardiac fibrosis, renal fibrosis, pancreatic fibrosis, skin fibrosis, intestinal fibrosis, ocular fibrosis, esophageal fibrosis, or combinations thereof.

3. The use according to claim 1, wherein, The prevention and / or treatment of fibrotic diseases includes one or more features selected from the group consisting of: (1) Reduce extracellular matrix proliferation and deposition; (2) Improve inflammation (reduce inflammatory factors such as IL-1β, IL-6, and CCL2); (3) Improve the molecular levels of fibrosis-related indicators (such as reducing hydroxyproline, α-SMA, COL-1 and / or Fibronectin levels); (4) Reduce tissue damage (protect the function of tissues and organs).

4. The use according to claim 1, wherein, The fibrotic disease mentioned is pulmonary fibrosis.

5. The use according to claim 1, wherein, The fibrotic disease mentioned is idiopathic pulmonary fibrosis.

6. The use according to claim 4, wherein, The prevention and / or treatment of pulmonary fibrosis includes one or more features selected from the group consisting of: Improve alveolar structure; Reduces the proliferation of mesenchymal cells in lung tissue; Reduce total cell count and LDH content in bronchoalveolar lavage fluid; Improves inflammation (reduces inflammatory factors such as IL-1β, IL-6, and CCL2); Reduce extracellular matrix proliferation and deposition; Reduce hydroxyproline content; Improve the molecular levels of fibrosis-related markers (such as reducing hydroxyproline, α-SMA, COL-1, and / or Fibronectin levels); and / or Reduce lung damage and improve lung function.

7. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is selected from the group consisting of: liquid preparations (such as solutions, emulsions, suspensions) and solid preparations (such as lyophilized preparations).

8. The use according to claim 1, wherein, The dosage form of the pharmaceutical composition is selected from the group consisting of: injections (such as solutions or powders for injection), oral preparations (such as capsules or tablets), microspheres or microcapsules for sustained release, liposomes, nanoparticles, and implants.

9. The use according to claim 1, wherein, The subjects were mammals.

10. The use according to claim 1, wherein, The subjects were humans, rats, or mice.

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