CN116098891A - Application of water-soluble vitamin E in treating lung injury and pulmonary fibrosis - Google Patents
Application of water-soluble vitamin E in treating lung injury and pulmonary fibrosis Download PDFInfo
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- CN116098891A CN116098891A CN202111320802.7A CN202111320802A CN116098891A CN 116098891 A CN116098891 A CN 116098891A CN 202111320802 A CN202111320802 A CN 202111320802A CN 116098891 A CN116098891 A CN 116098891A
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- water
- lung
- soluble vitamin
- pulmonary fibrosis
- fibrosis
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention belongs to the technical field of medicines, and discloses application of water-soluble vitamin E in preparation of a medicine for preventing and/or treating lung injury and pulmonary fibrosis. The invention discovers that the water-soluble vitamin E has the effect target of Galectin3 for the first time, has better application prospect in preparing medicaments for preventing and/or treating lung injury and pulmonary fibrosis, and has the characteristics of remarkable effect and small toxic and side effects.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of water-soluble vitamin E in preparing a medicine for preventing and/or treating lung injury and pulmonary fibrosis.
Background
The respiratory system is susceptible to various viral, bacterial infections and physicochemical injuries due to its physiological nature of exchanging gases with the outside world, thereby causing acute lung injury (Acute lung injury, ALI) and its severe acute respiratory distress syndrome (Acute respiratory distress syndrome, ARDS). ALI and ARDS pathological features are alveolar capillary, endothelial and alveolar epithelial cell injury, manifested by extensive pulmonary edema, micro-atelectasis, increased intra-pulmonary shunt and decreased lung compliance. Currently, for ALI, the treatment of ARDS mainly adopts glucocorticoid and respiratory machine auxiliary treatment, but sequelae such as diabetes, hypertension, femoral head necrosis and the like appear after many patients are healed, and the quality of life is seriously affected. Therefore, there is an urgent need to find drugs that are safe and effective in preventing and/or treating lung injury.
Pulmonary fibrosis (Pulmonary fibrosis, PF) is the end stage of all interstitial lung diseases (Interstitial lung Disease, ILD). PF is caused by various causes, and is mainly characterized by the aggregation of inflammatory cells such as macrophages, neutrophils and lymphocytes in alveoli and the accumulation of fibrous connective tissue in lung tissues, which finally results in the change of the lung tissue structure, the damage of the lung function and respiratory failure. In recent years, the incidence and mortality of pulmonary fibrosis have tended to rise year by year due to environmental and lifestyle factors.
Idiopathic pulmonary fibrosis (Idiopathic pulmonary fibrosis, IPF) is a relatively common type of PF, a chronic, progressive, interstitial fibrotic pulmonary disease. It is characterized in that the recurrent epithelial cell injury caused by unknown reasons, the aging of the alveolar epithelial cells, the aggregation of a fibrosis promoting medium and the like lead to the formation of progressive lung tissue scar. IPF patients have a survival period of only 2-6 years, typically 3 years, after diagnosis. Pirfenidone and nidanib were approved by the FDA in 2014 for IPF treatment, but it is also only possible to delay disease progression, and it is not known whether prolongation of survival can be achieved. Therefore, it is also important to find a safe and effective drug for preventing and/or treating the occurrence and development of pulmonary fibrosis.
Galectin-3 (Galectin-3) is a beta-galactoside binding lectin, often in homodimeric form, expressed mainly in tumor cells, macrophages, epithelial cells, fibroblasts and activated T cells. Are important in many biological activities of various organs, including cell proliferation, apoptosis regulation, inflammation, fibrosis, host defense, and the like. Galectin-3 is mainly present in cytoplasm, is expressed on cell nucleus and cell surface, and can be directly secreted into biological fluid such as serum, urine and tissue fluid by small bubbles. Many studies have shown that Galectin-3 can be an important biomarker for diagnosis or prognosis of myocardial fibrosis, kidney fibrosis, lung fibrosis, viral infection, autoimmune diseases, neurodegenerative diseases and neoplasia.
Therefore, inhibition of Galectin3 may be an effective scheme for preventing and/or treating lung injury and pulmonary fibrosis related diseases.
Disclosure of Invention
Aiming at the current situation of lack of safe and effective medicines for preventing and/or treating lung injury and pulmonary fibrosis, the invention provides an application of a compound water-soluble vitamin E targeting a Galectin3 signal pathway and pharmaceutically acceptable salts thereof in medicines for preventing and/or treating lung injury and pulmonary fibrosis, and provides a new way for treating lung injury and pulmonary fibrosis related diseases.
In order to achieve the above object, the present invention provides the following solutions:
the invention provides an application of water-soluble vitamin E and pharmaceutically acceptable salts thereof in preparation of Galectin3 inhibitors.
The second technical scheme of the invention is to provide the application of the water-soluble vitamin E and the pharmaceutically acceptable salt thereof in preparing the medicines for preventing and/or treating the lung injury diseases.
The "lung injury" as referred to herein may be acute lung injury or acute respiratory distress syndrome. The etiology of the lung injury disease includes lung injury caused by bacterial virus infection, gastroesophageal reflux, massive blood transfusion, drowning, shock, pancreatitis, lung contusion, excess salicylate anesthetic, alveolar hemorrhage, fat and amniotic fluid embolism, smoke and toxic gas inhalation, and the bacterial virus, such as lipopolysaccharide.
The third technical scheme of the invention is to provide the application of the water-soluble vitamin E and the pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating pulmonary fibrosis diseases.
The "pulmonary fibrosis" described in the present invention may be idiopathic pulmonary fibrosis or secondary pulmonary fibrosis. The etiology of the pulmonary fibrosis disease includes dust, radiation, and/or pulmonary fibrosis caused by drugs, such as bleomycin.
Further, the dosage forms of the inhibitor comprise injection, tablet, powder, granule, pill, capsule, oral liquid, ointment and cream.
Further, the pharmaceutical dosage forms comprise injection, tablet, powder, granule, pill, capsule, oral liquid, ointment and cream.
According to the present invention, the compound of the present invention may exist in the form of an isomer, and the general term "compound of the present invention" includes the isomer of the compound.
The invention also relates to a pharmaceutical composition comprising a pharmaceutically effective dose of said compound and a pharmaceutically acceptable carrier. For this purpose, if desired, it may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to form a suitable administration form or dosage form for use as a human medicament.
The pharmaceutical compositions of the present invention may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, dermal, peritoneal or rectal.
The route of administration of the pharmaceutical composition of the invention may be injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc. The dosage form may be a liquid dosage form or a solid dosage form. For example, the liquid dosage forms may be true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The composition of the invention can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the purpose of shaping the unit dosage form into a tablet, various carriers known in the art can be widely used. As examples of the carrier, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; humectants and binders such as water, gan Bo, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, gum arabic slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter and hydrogenated oils, and the like; absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or double and multi layered tablets.
For the preparation of the dosage unit into a pill, various carriers well known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, gelucire, kaolin and talc, etc.; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.
For preparing the dosage unit into suppositories, various carriers well known in the art can be widely used. Examples of carriers include polyethylene glycol, lecithin, cocoa butter, higher alcohols, enzymes of higher alcohols, gelatin, semisynthetic glycerases, and the like.
In order to capsule the dosage unit, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredients can also be made into microcapsule, suspension in aqueous medium to form suspension, or hard capsule or injection.
For example, the compositions of the invention are formulated for injection, such as solutions, suspension solutions, emulsions, freeze-dried powder injection solutions, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol, polyoxyethylene sorbitol lipase, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may be added to the pharmaceutical formulation as desired.
The dosage of the pharmaceutical composition of the present invention to be administered depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the administration route, the number of administrations and the like, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of the compounds of the present invention used are well known to those skilled in the art. The application of the invention in the preparation of medicines for preventing and/or treating pulmonary fibrosis and acute lung injury related diseases can be completed by properly adjusting the quantity of the actual effective medicines contained in the final preparation of the medicinal composition according to the invention so as to meet the requirement of the effective quantity.
In general, for patients weighing about 75 kg, the daily dose of the compound of the present invention is from 0.001mg/kg body weight to 200mg/kg body weight, preferably from 1mg/kg body weight to 100mg/kg body weight. The above-mentioned dosages may be administered in a single dosage form or in divided dosage forms, for example, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the administration regimen. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
The invention discloses the following technical effects:
the invention discovers that the compound water-soluble vitamin E, the action target Galectin3, has better application prospect in preparing medicaments for preventing and/or treating lung injury and pulmonary fibrosis, and has the characteristics of remarkable action effect and small toxic and side effects.
Drawings
FIG. 1 is a graph showing the weight change of mice in each group of lung injury models;
FIG. 2 is a graph showing the regulation of altered expression of genes associated with lung injury model inflammation by water-soluble vitamin E;
fig. 3 is a graph of pathological results of each group of lung injury models, fig. 3A is HE staining, and fig. 3B is Masson staining;
FIG. 4 is a graph showing the weight change of mice in each group of pulmonary fibrosis models;
FIG. 5 is a graph showing the regulation of inflammatory-related gene expression changes in a pulmonary fibrosis model by water-soluble vitamin E;
fig. 6 is a graph of pathological results of each group of lung fibrosis models, fig. 6A is HE staining, and fig. 6B is Masson staining.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
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 belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The "parts" in the present invention are all parts by mass unless otherwise specified.
Example 1 Effect of Water-soluble vitamin E on Galectin3 inhibitor model
1. The experimental materials of this example include:
experimental medicine: the water-soluble vitamin E is purchased from MCE company and has the structural formula:
test sample solution configuration: accurately weighing a proper amount of sample water-soluble vitamin E, preparing a storage solution of 0.02M by using DMSO, and testing the external activity of a donor.
Experimental reagent: MTT reagent is purchased from Beijing Soy Bao technology Co., ltd, 0.25g of MTT powder is accurately weighed, 50mL of PBS is added for dissolution, and after dissolution, the solution is filtered by a microporous filter membrane with the thickness of 0.22 mu m, and the solution is split-packed and stored at the temperature of minus 20 ℃.
Experimental instrument: a carbon dioxide incubator, panasonic company, japan; microplate reader, bio-tek company, usa; a Countstar automated cytometer, ai Lite life sciences (Shanghai); inverted microscope, niKon Corp; ultra clean bench, available from air technologies, inc. of Antai, china; 96 well culture plates (transparent plate and blackboard), corning company, usa.
Experimental cells: RAW264.7 cells were purchased from ATCC; a549 and MRC-5 cells were purchased from beijing synergetic cell resource center.
2. The experimental method comprises the following steps:
logarithmic growth of RAW264.7 and MRC-5 cells at 5X 10 3 Inoculating into 96-well plate (transparent plate) containing 5% CO 2 The culture medium is sucked off and washed 1 time by PBS, water-soluble vitamin E-containing culture medium with different concentrations is respectively added for continuous culture for 24 hours, the culture medium is removed, the PBS is washed 2 times, 0.1mL of serum-free culture medium containing 0.5mg/mL MTT is added, the culture medium is incubated for 3 hours in the incubator, the MTT solution is removed, 0.1mL of DMSO is added, the culture medium is placed on a shaker for 5 minutes by gentle shaking, and the absorbance is measured by an enzyme-labeled instrument (570/630 nm).
A549 cells in logarithmic growth phase were grown at 2X 10 4 The cells/wells were seeded in 96-well plates and placed in a solution containing 5% CO 2 Is cultivated in an incubator at 37 ℃ for 12 hours. Respectively adding water-soluble vitamin E culture media with different concentrations, continuously culturing for 2 hours, adding 1 mu m FITC-Galectin3 protein, incubating in a incubator for 2 hours, and detecting the fluorescence intensity by using a microplate reader 485/528 nm.
3. Experimental results:
the water-soluble vitamin E is nontoxic at the concentration of 10 mu m, and can significantly inhibit the binding of Galectin3 protein to cells, and the result is shown in Table 1.
Table 1 Compound cytotoxicity and Effect on Galectin3 inhibitor model
Example 2 Effect of Water-soluble vitamin E on lipopolysaccharide-induced lung injury model
1. The experimental materials of this example include:
experimental medicine:
test sample solution configuration: the water-soluble vitamin E is purchased from MCE company, and a proper amount of water-soluble vitamin E is accurately weighed and prepared into a 4mg/mL solution by water.
Dexamethasone solution configuration: dexamethasone tablets, 0.75 mg/tablet, manufactured by Tianjin Lisheng pharmaceutical Co., ltd, were formulated in water as a 0.045mg/mL solution.
Preparing lipopolysaccharide solution: lipopolysaccharide, purchased from Sigma-Aldrich, was formulated as a 20mg/mL stock solution in PBS and diluted to 0.2mg/mL in the clinic.
Hydroxyproline detection kit: purchased from the institute of bioengineering built in south Beijing.
Experimental animals:
SPF-class male C57BL/6J mice, 6-8 weeks old, weighing about 20g, purchased from Si Bei Fu (Beijing) Biotechnology Co., ltd., license number SCXK (Beijing) 2019-0010.
Experimental instrument: flexvent small animal pulmonary function system: flexiVent, SCIREQ Inc.
2. The experimental method comprises the following steps:
model construction:
a mouse acute lung injury model was constructed using intratracheal single injection of Lipopolysaccharide (LPS). The specific implementation is as follows: after the mice were anesthetized with tribromoethanol (400 mg/kg) after overnight fasted, LPS (0.5 mg/kg) was injected into the trachea by a noninvasive tracheal intubation technique in a volume of 50. Mu.L, and then the mice were rapidly stood and rotated to make LPS uniformly enter the lung lobes. Sham mice were intratracheal injected with an equal amount of PBS under the same anesthesia.
Experimental grouping and dosing:
mice were randomized into sham surgery group (PBS + saline), model group (LPS + saline), dexamethasone group (LPS + dexamethasone) and water-soluble vitamin E group (LPS + water-soluble vitamin E).
On the model day, the mice were given once daily for drug intervention after waking. The sham operation group and the model group are given with 0.1mL/10g physiological saline; dexamethasone groups were given by gavage with equal volumes of dexamethasone (0.45 mg/kg/d); the water-soluble vitamin E group is irrigated with the stomach to administer the water-soluble vitamin E (40 mg/kg/d) with equal volume; the administration was continued for 3 days while observing the general clinical symptoms of the mice.
TABLE 2 grouping of lung injury models and dosing regimen
Animal administration and material drawing:
after model and dosing feeding for 48 hours, fasted overnight, the next day, tribromoethanol anesthetized mice, and the alveolar lavage fluid of the mice was collected and the wet weight of the right middle lobe of the lung was weighed; placing the middle right lung leaf in a 60 ℃ constant temperature oven, baking for 48, weighing to obtain the dry weight of the middle right lung leaf, and calculating the lung wet weight ratio; the left large leaf of the lung is used for hydroxyproline determination; the upper right leaf of the lung is used for detecting relevant cytokines; lower right lung lobes were fixed, stained with HE and Masson. HE staining observed pathological morphology with simultaneous lung tissue fibrosis scoring. Pulmonary fibrosis grading scoring criteria: 0, occasional small increases in alveolar septum; no clear fibrosis was seen. 1, alveolar wall mild fibrous hyperplasia or bronchiolar wall mild fibrous hyperplasia. 2, the medium fibrous tissue hyperplasia of the alveoli wall or the medium fibrous tissue hyperplasia of the bronchiole wall does not occur the destruction of the lung tissue structure. 3, the medium fibrous tissue hyperplasia of the alveolar wall or the medium fibrous tissue hyperplasia of the bronchiole wall, a large amount of neutrophils and lymphocytes infiltrate, and the damage of the lung tissue structure is not seen. 4, small focal fibrous tissue hyperplasia accompanied by slight destruction of lung tissue structure. 5, focal fibrous tissue is obviously proliferated, the lung tissue structure is obviously destroyed, and fiber bundles are formed. And 6, carrying out platy fibrous tissue proliferation with serious damage to the pulmonary tissue structure. 7, diffuse vitamin tissue hyperplasia accompanied by serious destruction of lung tissue structure and formation of honeycomb lung. 8, obvious lung-excess changes. Masson staining selected 2 areas under 200-fold microscope to take pictures. Tissue area, fibrous tissue area and integrated absorbance (IOD) of fibrosis were measured using Image-Pro Plus 7.2 Image analysis software. The degree of fibrosis of the lung tissue and the average optical density of the fibrous tissue in each picture were calculated.
The statistical method comprises the following steps:
data are expressed as mean.+ -. Standard deviation (mean.+ -. SD), single-factor analysis of variance is used between groups, and p < 0.05 is statistically different. * Representing two corresponding groups of p < 0.05; * Representing that the corresponding two groups p < 0.01.
3. Experimental results:
(1) Effect of water-soluble vitamin E on physiological status of lung injury model mice:
cage side observations found that the model group showed symptoms of irritability, increased activity, shortness of breath, etc. from day 1, while the water-soluble vitamin E group and dexamethasone group were significantly lighter in symptoms than the model group. Body weight was monitored and mice significantly reduced after the model compared to sham-operated groups, but there was no significant difference between the water-soluble vitamin E group and dexamethasone group compared to the model group, and the results are shown in fig. 1.
(2) Effect of water-soluble vitamin E on respiratory inflammation in mice model of lung injury:
the wet/dry weight ratio of lung tissue may reflect the degree of lung tissue inflammation and edema. Protein exudation in alveolar lavage fluid reflects lung tissue inflammation and permeability. As can be seen from table 3, the lung wet weight/dry weight ratio and protein exudation were significantly increased in the mice of the model group compared to the sham group; and both water-soluble vitamin E and dexamethasone can obviously reduce the wet weight/dry weight ratio of lung and protein exudation.
TABLE 3 influence on pulmonary edema in lung injury models
In addition, the determination of key cytokines associated with inflammatory responses of lung tissue can more clearly describe the inflammatory response of the body caused by lipopolysaccharide. The results in FIG. 2 show that lipopolysaccharide results in significant increases in the expression levels of IL-1 beta, IL-6 and TNF-alpha mRNA in lung tissue, while both water-soluble vitamin E and dexamethasone significantly reduce the expression levels of IL-1 beta, IL-6 and TNF-alpha mRNA.
The results show that both water-soluble vitamin E and dexamethasone can significantly improve lipopolysaccharide-induced inflammatory response of lung tissue.
(3) Effect of Water-soluble vitamin E on pulmonary fibrosis in mice model of pulmonary injury
When the lung is fibrosed, the main components in the lung are collagen fibers, and the hydroxyproline is special for the collagen fibers, so that the content of the hydroxyproline in the lung can be measured, and the collagen content of the lung tissue can be reflected, and further the fibrosis degree of the lung tissue can be reflected. The results in table 4 show that the hydroxyproline content in the lung tissue of mice in the model group is significantly increased compared to the sham surgery group; and the water-soluble vitamin E or dexamethasone can obviously reduce the hydroxyproline content of the lung tissue of the mice.
To visually examine the morphological changes of the lung tissue of the mice, HE staining was performed on the lung tissue, and as can be seen from fig. 3A, the morphological structure of the lung tissue of the sham surgery group was not significantly changed; the model group lung tissue is widely fibrosed, locally becomes solid, is diffusely infiltrated by a large number of lymphocytes and neutrophils, the residual alveoli are slightly expanded, the whole lung tissue is cellular, the epithelium of the local alveoli is obviously atrophic and disappears, and the lung tissue structure is seriously destroyed; the above pathological changes of the water-soluble vitamin E group and dexamethasone group are obviously improved, but the pathological changes are also obviously different from those of the false operation group. Performing fibrosis scoring with reference to a pulmonary fibrosis grading scoring criteria, wherein the model group mice have significantly increased fibrosis scores compared to the sham surgery group; compared with the model group, the water-soluble vitamin E and dexamethasone can obviously reduce the pulmonary fibrosis score, and the results are shown in Table 4.
Masson staining can measure the fibrous tissue area and the integrated absorbance of fibrosis, reflecting the degree of fibrosis in lung tissue and the degree of dense fibrous tissue proliferation. Fig. 3B is a set of typical Masson-stained pictures taken. From fig. 3B, it can be seen that the lung tissue of sham mice contains a small amount of collagen fibers, which are the major components of the extracellular matrix; the collagen fibers of mice in the model group are obviously increased, the density degree of fibrous tissue hyperplasia is obviously increased, and typical pulmonary interstitial fibrosis occurs; pulmonary interstitial fibrosis changes also occurred in the water-soluble vitamin E group and the dexamethasone group, but the areas of collagen fibers and the density of fibrous tissue hyperplasia of the lung tissues of the water-soluble vitamin E group and the dexamethasone group were reduced compared with the model group. From the quantification results in table 4, both water-soluble vitamin E and dexamethasone significantly reduced the fibrosis area and fibrosis density compared to the model group.
TABLE 4 effects on pulmonary fibrosis in lung injury models
The above results indicate that both water-soluble vitamin E and dexamethasone significantly improve lipopolysaccharide-induced pulmonary fibrosis.
Example 3 Effect of Water-soluble vitamin E on bleomycin-induced pulmonary fibrosis model
1. The experimental materials of this example include:
experimental medicine:
test sample solution configuration: the water-soluble vitamin E is purchased from MCE company, and a proper amount of water-soluble vitamin E is accurately weighed and prepared into a 4mg/mL solution by water.
Dexamethasone solution configuration: dexamethasone tablets, 0.75 mg/tablet, manufactured by Tianjin Lisheng pharmaceutical Co., ltd, were formulated into a 0.045mg/mL solution with physiological saline.
Bleomycin solution configuration: bleomycin hydrochloride for injection, 15U/min, produced by Hanhui pharmaceutical Co., ltd, is prepared into 100U/mL stock solution by PBS and is diluted for use.
Hydroxyproline detection kit: purchased from the institute of bioengineering built in south Beijing.
Experimental animals:
SPF-class male C57BL/6J mice, 6-8 weeks old, weighing about 20g, purchased from Si Bei Fu (Beijing) Biotechnology Co., ltd., license number SCXK (Beijing) 2019-0010.
Experimental instrument:
flexvent small animal pulmonary function system: flexvent, SCIREQ Inc.
2. The experimental method comprises the following steps:
model construction:
a mouse lung fibrosis model was constructed using a single intratracheal injection of Bleomycin (BLM). The specific implementation is as follows: after the mice were fasted overnight and anesthetized with tribromoethanol (400 mg/kg), bleomycin (3U/kg) was injected intratracheally using a non-invasive tracheal intubation technique, at a volume of 50. Mu.L, and then the mice were rapidly stood and rotated to allow BLM to enter evenly into the lobes of the lung. Sham mice were intratracheal injected with an equal amount of PBS under the same anesthesia.
Experimental grouping and dosing:
mice were randomized into sham surgery (PBS + saline), model (BLM + saline), dexamethasone (BLM + dexamethasone) and water-soluble vitamin E (BLM + water-soluble vitamin E).
On the model day, the mice were given once daily for drug intervention after waking. The sham operation group and the model group are given with 0.1mL/10g physiological saline; dexamethasone groups were given by gavage with equal volumes of dexamethasone (0.45 mg/kg/d); the water-soluble vitamin E group is irrigated with the stomach to administer the water-soluble vitamin E (40 mg/kg/d) with equal volume; the administration was continued for 21 days while observing the general clinical symptoms of the mice.
TABLE 5 grouping of pulmonary fibrosis models and dosing regimen
Animal material selection:
model and dosing 21 days later, the mice were fasted overnight, the mice were anesthetized with tribromoethanol, the pulmonary function was examined, the lung weights were weighed, and the lung index was calculated (lung index = lung weight (g)/body weight (g) ×100%); the left large leaf of the lung is used for hydroxyproline determination; the upper right leaf of the lung is used for detecting relevant cytokines; lower right lung lobes were fixed, stained with HE and Masson. HE staining observed pathological morphology with simultaneous lung tissue fibrosis scoring. Pulmonary fibrosis grading scoring criteria: 0, occasional small increases in alveolar septum; no clear fibrosis was seen. 1, alveolar wall mild fibrous hyperplasia or bronchiolar wall mild fibrous hyperplasia. 2, the medium fibrous tissue hyperplasia of the alveoli wall or the medium fibrous tissue hyperplasia of the bronchiole wall does not occur the destruction of the lung tissue structure. 3, the medium fibrous tissue hyperplasia of the alveolar wall or the medium fibrous tissue hyperplasia of the bronchiole wall, a large amount of neutrophils and lymphocytes infiltrate, and the damage of the lung tissue structure is not seen. 4, small focal fibrous tissue hyperplasia accompanied by slight destruction of lung tissue structure. 5, focal fibrous tissue is obviously proliferated, the lung tissue structure is obviously destroyed, and fiber bundles are formed. And 6, carrying out platy fibrous tissue proliferation with serious damage to the pulmonary tissue structure. 7, diffuse vitamin tissue hyperplasia accompanied by serious destruction of lung tissue structure and formation of honeycomb lung. 8, obvious lung-excess changes. Masson staining selected 2 areas under 200-fold microscope to take pictures. Tissue area, fibrous tissue area and integrated absorbance (IOD) of fibrosis were measured using Image-Pro Plus 7.2 Image analysis software. The degree of fibrosis of the lung tissue and the average optical density of the fibrous tissue in each picture were calculated.
The statistical method comprises the following steps:
data are expressed as mean.+ -. Standard deviation (mean.+ -. SD), single-factor analysis of variance is used between groups, and p < 0.05 is statistically different. * Representing two corresponding groups of p < 0.05; * Representing that the corresponding two groups p < 0.01.
3. Experimental results:
(1) Effect of Water-soluble vitamin E on physiological State of Lung fibrosis model mice
Cage side observation shows that the model group mice show symptoms such as hair color difference, hair frying, irritability, activity increase, shortness of breath and the like from the 5 th day; the dexamethasone and water-soluble vitamin E groups were significantly less symptomatic than the model group. Monitoring the weight of the mice, and finding that the weight of the mice is obviously reduced after molding, and the mice start to have an ascending trend after 6 days; the dexamethasone group weight is reduced more obviously; while the water-soluble vitamin E group was not significantly different from the model group, the results are shown in fig. 4. The survival rate was counted, as shown in table 6, and at 21 days, the survival rate of the sham operation group was 100%, the survival rate of the model group was 75%, the survival rate of the water-soluble vitamin E group was 75%, and the survival rate of the dexamethasone group was 66.66%.
TABLE 6 influence on survival of pulmonary fibrosis model mice
(2) Effect of Water-soluble vitamin E on respiratory function in Lung fibrosis model mice
The respiratory system function of the mice is detected by using a Flexvent small animal lung function system. The impaired respiratory function of the mice is judged by respiratory resistance (Rrs), respiratory elasticity (Ers) and respiratory compliance (Crs).
As can be seen from table 7, bleomycin can induce significant impairment of respiratory function in mice, manifested by significant increases in respiratory resistance and respiratory elasticity and significant decreases in respiratory compliance; the water-soluble vitamin E and dexamethasone can obviously improve the indexes, and the respiratory resistance is close to the level of a false operation group. The results show that both the water-soluble vitamin E and dexamethasone can significantly improve bleomycin-induced respiratory function injury of mice.
TABLE 7 influence on pulmonary fibrosis model pulmonary function
The above results indicate that water-soluble vitamin E can significantly improve bleomycin-induced respiratory function impairment in mice.
(3) Effect of Water-soluble vitamin E on pulmonary fibrosis model mouse respiratory inflammation
The determination of key cytokines in the inflammatory response of lung tissue may describe the inflammatory response of the body by bleomycin. The results in FIG. 5 show that bleomycin results in significant increases in lung tissue inflammatory factor IL-1β, IL-6 and TNF- α mRNA expression, whereas both water-soluble vitamin E and dexamethasone significantly reduce IL-1β, IL-6 and TNF- α mRNA expression, approaching that of the sham group. The results show that both water-soluble vitamin E and dexamethasone can significantly improve bleomycin-induced inflammatory response of lung tissue.
(4) Effect of Water-soluble vitamin E on pulmonary fibrosis model mice pulmonary fibrosis
The lung index may reflect the degree of lung tissue fibrosis in lung fibrosis model mice. As can be seen from table 8, the lung index of the mice in the model group was significantly increased compared to the sham group; the water-soluble vitamin E can obviously reduce the lung index; there was only a trend in the dexamethasone group.
When the lung is fibrosed, the main components in the lung are collagen fibers, and the hydroxyproline is special for the collagen fibers, so that the content of the hydroxyproline in the lung can be measured, and the collagen content of the lung tissue can be reflected, and further the fibrosis degree of the lung tissue can be reflected. As can be seen from table 8, the hydroxyproline content of mice in the model group was significantly increased compared to the sham group; the water-soluble vitamin E and dexamethasone can obviously reduce the content of hydroxyproline.
To visually examine the morphological changes of the lung tissue of the mice, HE staining was performed on the lung tissue, and as can be seen from fig. 6A, the morphological structure of the lung tissue of the sham surgery group was not significantly changed; model group pulmonary interstitial blood vessel congestion, alveolar space wide broadening, alveolar space shrinking, local lamellar pulmonary fibrosis, severe destruction of pulmonary tissue structure, diffuse infiltration of a large number of lymphocytes, plasma cells and neutrophils at lesion sites; the pathological changes of dexamethasone and water-soluble vitamin E groups were alleviated, but there were also significant differences from the sham-operated group.
Scoring the lung tissue of the mice with reference to a lung fibrosis grading scoring criteria, wherein the model group mice have significantly increased fibrosis scores compared to the sham group; the water-soluble vitamin E significantly reduced the fibrosis score, with no significant decrease in the dexamethasone group, and the results are shown in table 8.
Masson staining can measure the fibrous tissue area and the integrated absorbance of fibrosis, reflecting the degree of fibrosis in lung tissue and the degree of dense fibrous tissue proliferation. Fig. 6B is a set of typical Masson-stained pictures taken. From fig. 6B, it can be seen that the lung tissue of sham mice contains a small amount of collagen fibers, which are the major components of the extracellular matrix; the collagen fibers of mice in the model group are obviously increased, the density degree of fibrous tissue hyperplasia is obviously increased, and typical pulmonary interstitial fibrosis occurs; pulmonary interstitial fibrosis changes also occurred in the dexamethasone and water-soluble vitamin E groups, but the degree of fibrosis was reduced compared to the model group. From the quantitative results in table 8, water-soluble vitamin E significantly reduced the fibrosis area and fibrosis density compared to the model group, and dexamethasone also had a trend toward lower, but slightly less effective, groups.
TABLE 8 influence on pulmonary fibrosis model pulmonary tissue fibrosis
The results show that both the water-soluble vitamin E and the dexamethasone can obviously improve the bleomycin-induced pulmonary fibrosis, and the effect of the water-soluble vitamin E is slightly better than that of the dexamethasone.
From the experimental results, the water-soluble vitamin E can obviously reduce pulmonary alveoli inflammation, interstitial pulmonary inflammation and collagen deposition of pulmonary tissues of a lipopolysaccharide-induced lung injury model mouse; the pulmonary interstitial inflammation and the pulmonary tissue fibrosis degree of the bleomycin-induced pulmonary fibrosis model mice are obviously reduced. Thereby reducing the degree of lung injury, preventing and treating pulmonary fibrosis, improving lung function and increasing survival rate.
The water-soluble vitamin E has good effects of preventing and treating lung injury and pulmonary fibrosis, and the effect is slightly better than that of dexamethasone.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (5)
1. The application of water-soluble vitamin E shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing Galectin3 inhibitor;
2. the application of water-soluble vitamin E shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing medicaments for preventing and/or treating lung injury diseases;
3. the use according to claim 2, wherein the lung injury is acute lung injury or acute respiratory distress syndrome.
4. The application of water-soluble vitamin E shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating pulmonary fibrosis diseases;
5. the use according to claim 4, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis or secondary pulmonary fibrosis.
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