Application of metabolites in the preparation of drugs for preventing or treating bronchopulmonary dysplasia

Abstract

The present application relates to the use of a metabolite in the preparation of a drug for preventing or treating bronchopulmonary dysplasia, wherein the metabolite is 4-amino-4'-methoxydiphenylamine. The present application finds that 4-amino-4'-methoxydiphenylamine can repair mitochondrial damage in Cdkn1a+ transitional cells, promote their differentiation into AT1, and improve alveolar development in BPD.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to the use of metabolites in the preparation of drugs for preventing or treating bronchopulmonary dysplasia. Background Art

[0002] Bronchopulmonary dysplasia (BPD) is a common adverse outcome in premature infants, and the incidence rate increases with gestational age. Currently, clinical treatment measures for BPD mainly include oxygen supplementation, glucocorticoids, and surfactants, but excessive oxygen supplementation is also a driving factor for alveolar development blockage in BPD; although the use of glucocorticoids and surfactants can improve alveolar development, glucocorticoids are associated with many adverse events such as hypertension and hyperglycemia, and surfactants are expensive.

[0003] BPD often occurs in premature infants, especially extremely low birth weight infants, who are still accompanied by severe lung immaturity at birth. The improvement of alveolar development is the key for newborns to adapt to the external environment and perform autonomous breathing. In the lungs, type 1 alveolar epithelial cells (AT1) form the interface for gas exchange in the alveoli, but most AT1s have no autonomous renewal and differentiation ability, while type 2 alveolar epithelial cells (AT2) as a stem cell population can differentiate into AT1 to achieve terminal development of alveoli. Most Cdkn1a+ transitional cells originate from AT2; as the alveoli develop after birth, these transitional cells gradually differentiate into AT1, and the differentiation disorder of Cdkn1a+ transitional cells to AT1 may lead to the blockage of alveolar development in BPD. Therefore, promoting the differentiation of Cdkn1a+ transitional cells to AT1 is an important direction for finding effective prevention and treatment of BPD, and is expected to provide new intervention methods for the treatment of BPD. Summary of the invention

[0004] Based on this, it is necessary to provide an embodiment of the present application for the use of a metabolite in the preparation of a drug for preventing or treating bronchopulmonary dysplasia.

[0005] The technical solutions include the following:

[0006] The invention discloses an application of a metabolite in preparing a drug for preventing or treating bronchopulmonary dysplasia, wherein the metabolite is 4-amino-4'-methoxydiphenylamine.

[0007] In one embodiment, the bronchopulmonary dysplasia comprises one or more of the following features:

[0008] (1) Alveolar development blockage;

[0009] (2) differentiation disorder of Cdkn1a+ transitional cells into AT1 cells;

[0010] (3) mitochondrial damage in Cdkn1a+ migratory cells; and

[0011] (4) Abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ migratory cells;

[0012] In one embodiment, the alveolar development block includes alveolar simplification, reduced alveolar number and widened alveolar septa.

[0013] In one embodiment, the drug repairs mitochondrial damage in Cdkn1a+ transitional cells.

[0014] In one embodiment, the drug improves the abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ transitional cells.

[0015] In one embodiment, the drug promotes the differentiation of Cdkn1a+ transitional cells into AT1 cells.

[0016] In one embodiment, the medicament improves alveolar development in bronchopulmonary dysplasia.

[0017] In one embodiment, the drug improves alveolar simplification, reduction in alveolar number, and widening of alveolar septa.

[0018] In one embodiment, the drug comprises an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the metabolite.

[0019] In one embodiment, the auxiliary material includes at least one of a filler, a binder, a wetting agent, a disintegrant, a lubricant, a solubilizer, a pH adjuster and a flavoring agent.

[0020] In one embodiment, the dosage form of the drug includes injection, oral solution, pill, powder, paste, tablet, granule, powder or capsule.

[0021] Compared with the traditional technology, this application has the following beneficial effects:

[0022] The present application found that 4-amino-4'-methoxydiphenylamine can repair mitochondrial damage in Cdkn1a+ transitional cells, promote their differentiation into AT1, and improve alveolar development in BPD. This small molecule metabolite has good properties such as small molecular weight and high stability, and can be used as a potential good drug for the treatment of BPD, with good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0024] Figure 1 The Cdkn1a+ transitional cells in the BPD cell model constructed under hyperoxia, and the JC-1 status of the Cdkn1a+ transitional cells under HAB intervention; the left side is the Con group, the middle is the BPD group, and the right side is the BPD+HAB group. The results show that HAB can improve the mitochondrial damage of Cdkn1a+ transitional cells in the BPD cell model induced by hyperoxia;

[0025] Figure 2 The electron microscopy of mitochondria of Cdkn1a+ transitional cells in the BPD cell model constructed by hyperoxia and HAB intervention. The left side is the Con group, the middle is the BPD group, and the three pictures on the right are the BPD+HAB group. The results show that HAB can improve the mitochondrial morphology of Cdkn1a+ transitional cells in BPD model mice and change their mitochondrial distribution.

[0026] Figure 3 The HAB intervention BPD animal model, lung tissue was extracted on the 7th day of modeling and intervention. The left side is the Con group, the middle is the BPD group, and the right side is the BPD+HAB group. The results of immunofluorescence co-staining showed that the differentiation of Cdkn1a+ transitional cells into AT1 was significantly increased in the HAB treatment group compared with the modeling group.

[0027] Figure 4 The HAB intervention BPD animal model, lung tissue was extracted on the 7th day of modeling and intervention. The left side is the Con group, the middle is the BPD group, and the right side is the BPD+HAB group. The results of H&E staining showed that HAB intervention can significantly improve BPD-like alveolar development blockage such as alveolar simplification, reduced alveolar number, and widened alveolar septa. DETAILED DESCRIPTION

[0028] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific implementation methods of the present application are described in detail below. In the following description, many specific details are set forth to facilitate a full understanding of the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present application, so the present application is not limited by the specific embodiments disclosed below.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0030] In this document, exemplary descriptions such as "in some implementation modes (or examples)" and "in one of the implementation modes (or examples)" may include but are not limited to the following meanings: these solutions may be combined with other solutions in a suitable manner to form a new technical solution.

[0031] In this application, "optionally", "optional", and "optional" refer to being optional, that is, to being selected from either of the two parallel schemes of "yes" or "no". If multiple "optional" items appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" item is independent of each other. Unless otherwise specified, descriptions such as "optionally include" and "optionally contain" in this application, taking "optionally include" as an example, mean "may include or not include". "Optional component X" means that component X exists or does not exist.

[0032] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items. "Any and all combinations" include any combination of two related listed items, any more related listed items, or all related listed items. For example, "A and / or B" includes three parallel solutions: A, B, and "a combination of A and B".

[0033] The terms "multiple", "multiple", "multiple times", "multiple", "several", etc. mentioned herein, unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0034] The terms "contain", "include" and "include" used in this application are synonymous, which are inclusive or open-ended and do not exclude additional, uncited members or features. Members or features include materials or components, structures, elements, instruments, etc.; non-limiting examples of members or features include actions, conditions for the occurrence of actions, timing, states, etc.

[0035] In this article, BPD: bronchopulmonary dysplasia.

[0036] In this paper, C 13 H 14 N2O: 4-amino-4'-methoxydiphenylamine.

[0037] In this article, Cdkn1a+ transitional cells: transitional alveolar epithelial cells in AT2 and AT1 during mouse embryos, expressing Sftpc, Hopx, and Cdkn1a.

[0038] In this article, AT1: alveolar type I epithelial cell.

[0039] Herein, AT2: alveolar type II epithelial cell.

[0040] In this article, Sftpc: pulmonary surfactant protein C, mainly expressed in AT2.

[0041] In this article, Hopx: homeodomain-specific protein, mainly expressed in AT1.

[0042] In this article, Con group: control group.

[0043] In this article, MAN: alveolar number.

[0044] In this article, MIL: alveolar mean linear intercept.

[0045] In this article, JC-1 detection: JC-1 is an ideal fluorescent probe widely used to detect mitochondrial membrane potential. It can detect the mitochondrial membrane potential of cells, tissues or purified mitochondria. When the mitochondrial membrane potential is high, JC-1 aggregates in the matrix of mitochondria to form polymers, which can produce red fluorescence; when the mitochondrial membrane potential is low, JC-1 cannot aggregate in the matrix of mitochondria. At this time, JC-1 is a monomer and can produce green fluorescence. In this way, it is very convenient to detect changes in mitochondrial membrane potential by changing the fluorescence color. The relative ratio of red and green fluorescence is often used to measure the proportion of mitochondrial depolarization.

[0046] In one embodiment of the present application, a metabolite is provided for use in the preparation of a drug for preventing or treating bronchopulmonary dysplasia, wherein the metabolite is 4-amino-4'-methoxydiphenylamine. The metabolite is obtained by screening the metabolites of Cdkn1a+ transitional cells in a normal group and a BPD animal model group using non-targeted metabolomics technology, and its molecular formula is C 13 H 14 N2O, with a molecular weight of 214.26, is an amide derivative of α-amino acid, which is referred to as HAB in this application.

[0047] The present application found that the molecular metabolite can repair mitochondrial damage in Cdkn1a+ transitional cells, promote their differentiation into AT1, and improve alveolar development in BPD. The small molecule metabolite has good properties such as small molecular weight and high stability, and can be used as a potential good drug for the treatment of BPD, with good application prospects.

[0048] In one specific example, bronchopulmonary dysplasia includes one or more of the following features:

[0049] (1) Alveolar development blockage;

[0050] (2) differentiation disorder of Cdkn1a+ transitional cells into AT1 cells;

[0051] (3) mitochondrial damage in Cdkn1a+ migratory cells;

[0052] (4) Abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ migratory cells.

[0053] BPD hinders normal alveolar development, resulting in damage to alveolar epithelial cells and basement membranes and abnormal repair after damage, which ultimately leads to BPD pathophysiological changes such as a decrease in the number of alveoli, an increase in volume, and a simplified structure. Alveolar development blockage is a complex process that includes damage to alveoli and abnormal repair after damage.

[0054] In one specific example, the alveolar development block includes alveolar simplification, a decrease in the number of alveoli, and widening of the alveolar septa.

[0055] In one specific example, the prevention or treatment refers to repairing mitochondrial damage in Cdkn1a+ migratory cells.

[0056] In a specific example, prevention or treatment refers to improving abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ transitional cells.

[0057] In the cell experiment of the present application, adding HAB to the cell culture medium of Cdkn1a+ transitional cells in the BPD cell model can repair damaged mitochondria. The JC-1 experiment confirmed that HAB can improve the mitochondrial damage of Cdkn1a+ transitional cells in the BPD cell model induced by hyperoxia. Mitochondrial transmission electron microscopy showed that HAB can improve the mitochondrial morphology of BPD Cdkn1a+ transitional cells and change their mitochondrial distribution. Among them, BPD Cdkn1a+ transitional cells are Cdkn1a+ transitional cells induced by hyperoxia.

[0058] Low HAB content is the key to inducing mitochondrial damage in Cdkn1a+ transitional cells in the BPD cell model, and increasing HAB content can repair damaged mitochondria.

[0059] In a specific example, the prevention or treatment refers to promoting the differentiation of Cdkn1a+ transitional cells into AT1 cells in BPD.

[0060] In one specific example, preventing or treating refers to improving alveolar development in bronchopulmonary dysplasia.

[0061] In one embodiment, prevention or treatment refers to improving alveolar simplification, reduction in the number of alveoli, and widening of the alveolar septa.

[0062] In the animal experiment of the present application, a BPD animal model was constructed in young mice through hyperoxia modeling, and it was found that HAB intervention can significantly promote the differentiation of Cdkn1a+ transitional cells to AT1 in the BPD animal model; and HAB intervention can significantly improve BPD-like alveolar developmental blockade such as alveolar simplification, reduced alveolar number and widened alveolar septa.

[0063] In a specific example, the drug includes an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient includes the metabolite.

[0064] In a specific example, the excipients include, but are not limited to, one or more of a filler, a binder, a wetting agent, a disintegrant, a lubricant, a solubilizer, a flavoring agent, and a pH adjuster.

[0065] In a specific example, the filler includes, but is not limited to, one or more of starches, sugars, celluloses, and inorganic salts.

[0066] In a specific example, the humectant includes, but is not limited to, one or more of water, ethanol, glycerin, and propylene glycol.

[0067] In a specific example, the disintegrant is one or more of, but not limited to, starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium dicarboxymethyl cellulose, crospovidone, a surfactant, and a runt disintegrant.

[0068] In a specific example, the binder includes, but is not limited to, one or more of sodium carboxymethyl cellulose, povidone K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hypromellose and gelatinized starch.

[0069] In a specific example, the lubricant includes, but is not limited to, one or more of talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micronized silica gel, and polyethylene glycol.

[0070] In a specific example, the solubilizing agent includes, but is not limited to, one or more of Tweens, sorbits, polyoxyethylene fatty alcohol ethers, soaps, sulfates, and sulfonates.

[0071] In a specific example, the flavoring agent includes, but is not limited to, one or more of a colorant, a flavoring agent, a sweetener, a gum agent, and a flavoring agent.

[0072] In a specific example, the pH adjuster includes, but is not limited to, one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, and citrates.

[0073] It should be noted that in the preparation process of drug preparations, appropriate excipients are selected based on multiple factors such as the properties of the drug, the requirements of the preparation, and the production process.

[0074] In a specific example, the dosage form of the drug includes, but is not limited to, injection, oral solution, pill, powder, paste, tablet, granule, powder or capsule.

[0075] An embodiment of the present application also provides a drug for preventing or treating bronchopulmonary dysplasia, the drug comprising an active ingredient and a pharmaceutically acceptable excipient.

[0076] In one specific example, the active ingredient includes the above-mentioned metabolite.

[0077] Optionally, the pharmaceutically acceptable excipients are the same as described above.

[0078] One embodiment of the present application also provides a method for promoting the differentiation of Cdkn1a+ transitional cells into AT1, comprising using the above-mentioned metabolites to promote the differentiation of Cdkn1a+ transitional cells into AT1.

[0079] The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0080] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0081] The small molecule metabolite HAB involved in the following examples is a commercial product with a molecular formula of C 13 H 14 N2O, molecular weight 214.26, chemical structure formula: , which is an amide derivative of α-amino acid.

[0082] The JC-1 detection kit in the following examples was purchased from Shanghai Biyuntian Co., Ltd.

[0083] The Cdkn1a+ transitional cells used in the following examples are alveolar Cdkn1a+ transitional cells from normal mice. Cdkn1a+ cells are transitional cells between AT2 and AT1, characterized by co-expression of sftpc, hopx, and Cdkn1a. Cells co-expressing sftpc, hopx, and Cdkn1a are sorted out by flow sorting technology, which are Cdkn1a+ transitional cells. Conditions for establishing the BPD cell model: Cdkn1a+ transitional cells are cultured in a high oxygen chamber with 85% O2, a 37°C incubator, and high oxygen and the small molecule metabolite are intervened simultaneously for 24 hours; grouping: Con group, BPD group, BPD+HAB group, and other culture conditions are the same.

[0084] The animals used in the following examples are newborn SD rats. The conditions for establishing the BPD model mice are as follows: Newborn SD rats were placed in an 85% hyperoxia chamber after intraperitoneal injection of the small molecule metabolite, and the hyperoxia environment and normoxia environment were alternated for 12 hours, and the intraperitoneal injection was repeated once before each hyperoxia (50 μg / kg HAB was injected in the BPD+HAB group), and the effect lasted for 7 days; the groups were divided into: Con group, BPD group, BPD+HAB group, and other culture conditions were the same.

[0085] The main detection methods involved in the following embodiments include:

[0086] Immunofluorescence co-staining: Wash the slides with cells in the culture plate with PBS 3 times, 5 minutes each time. Fix the slides with 4% paraformaldehyde for 15 minutes, and wash the slides with PBS 3 times, 5 minutes each time. Permeabilize with 0.5% Triton X-100 (prepared in PBS) at room temperature for 20 minutes, wash the slides with PBS 3 times, 5 minutes each time, dry the PBS with absorbent paper, and add blocking solution to the slides for 30 minutes at room temperature. Absorb the blocking solution with absorbent paper, add diluted primary antibody (Hopx) to each slide and put it in a wet box, and incubate overnight at 4°C. Wash the slides with PBST 3 times, 5 minutes each time, dry the excess liquid on the slides with absorbent paper, and add diluted fluorescent secondary antibody, incubate in a wet box for 1 hour, and wash the sections with PBST 3 times, 5 minutes each time. Incubate Sftpc and Cdkn1a according to the above steps. DAPI was added and incubated for 5 min in the dark to stain the nucleus of the specimen, and the excess DAPI was washed off with PBST for 5 min × 4 times. After drying with absorbent paper, the specimen was sealed with sealing solution containing anti-fluorescence quenching agent, and then the image was observed and collected under a fluorescence microscope.

[0087] H&E staining: Put the slices into environmentally friendly dewaxing solution I for 20 minutes, environmentally friendly dewaxing solution II for 20 minutes, anhydrous ethanol I for 5 minutes, anhydrous ethanol II for 5 minutes, and 75% alcohol for 5 minutes, and wash with tap water. Take the frozen slices out of the -20° refrigerator and restore them to room temperature. Fix them with tissue fixative for 15 minutes and rinse with running water. Put the slices into high-definition constant staining pretreatment solution for 1 minute. Slices are dyed in hematoxylin staining solution for 3-5 minutes, washed with tap water, differentiated with differentiation solution, washed with tap water, blued with blue reversion solution, and rinsed with running water. Dehydrate the slices in 95% alcohol for 1 minute and stain them in eosin staining solution for 15 seconds. Put the slices into anhydrous ethanol I for 2 minutes - anhydrous ethanol II for 2 minutes - anhydrous ethanol III for 2 minutes - n-butanol I for 2 minutes - n-butanol II for 2 minutes - xylene I for 2 minutes - xylene II for 2 minutes to make them transparent, and seal them with neutral gum. Microscope examination, image acquisition and analysis.

[0088] Example 1

[0089] The JC-1 method was used to detect the effect of HAB on mitochondria of Cdkn1a+ transitional cells in the BPD cell model.

[0090] Cdkn1a+ transitional cells were taken as the research object. Cdkn1a+ transitional cells were inoculated and subcultured into 6-well plates. Cdkn1a+ transitional cells were cultured in a 37℃, 85% O2 high oxygen chamber, and 5% CO2 incubator. Con group, BPD group, and BPD+HAB group were set up, with 3 replicates in each group. After culturing until adherence, HAB with a final concentration of 50μM was added to the BPD+HAB group, and the same volume of water was added to the Con group and BPD group, respectively. After 24 hours of intervention, the JC-1 detection kit was used to detect the effect of HAB on the mitochondria of Cdkn1a+ transitional cells treated with hyperoxia.

[0091] like Figure 1 As shown, HAB can improve mitochondrial damage in Cdkn1a+ migratory cells in the hyperoxia-induced BPD cell model.

[0092] Example 2

[0093] Transmission electron microscopy was used to detect the mitochondrial morphology of Cdkn1a+ migratory cells.

[0094] Cdkn1a+ transitional cells were taken as the research object. Cdkn1a+ transitional cells were inoculated and subcultured into 6-well plates. Cdkn1a+ transitional cells were cultured in a 37℃, 85% O2 high oxygen chamber, 5% CO2 incubator. Con group, BPD group, and BPD+HAB group were set up, with 3 replicates in each group. HAB was added after culture until adherence. After intervention for 24 hours, the cells were fixed with 5% pre-cooled glutaraldehyde and sent for inspection.

[0095] like Figure 2As shown, HAB can improve the mitochondrial morphology and change the mitochondrial distribution of Cdkn1a+ transitional cells in the BPD cell model.

[0096] Example 3

[0097] Immunofluorescence co-staining was used to detect the effect of HAB on the differentiation of Cdkn1a+ transitional cells in SD mice under hyperoxic environment.

[0098] To construct a BPD model, SD rat pups were taken one day after birth and placed in an 85% hyperoxia chamber. The rats were placed in a hyperoxic environment for 12 hours and a normoxic environment for 12 hours alternately. The rats were intraperitoneally injected once before each hyperoxia. The rats were divided into Con group, BPD group, and BPD+HAB group. Other culture conditions were the same. After 7 days of exposure, the lung tissues of the rat pups were obtained, sliced, and subjected to immunofluorescence co-staining experiments.

[0099] like Figure 3 As shown in the figure, immunofluorescence co-staining experiments showed that after HAB intervention, the differentiation of Cdkn1a+ transitional cells into AT1 was significantly increased in the HAB treatment group compared with the modeling group, indicating that HAB can promote AT1 differentiation and thus improve alveolar development in BPD.

[0100] Example 4

[0101] H&E staining was used to detect the effect of HAB on alveolar development in SD rat pups in a hyperoxic environment.

[0102] To construct a BPD model, SD rat pups at day 1 were placed in an 85% hyperoxia chamber and alternated between 12 h of hyperoxia and 12 h of normoxia. Intraperitoneal injection was repeated before each hyperoxia. The rats were divided into Con group, BPD group, and BPD+HAB group. Other culture conditions were the same. After 7 days of action, lung tissues of the pups were obtained, sliced, and subjected to H&E staining experiments.

[0103] The results showed that Figure 4 As shown in the results of H&E staining experiments, HAB intervention can significantly improve BPD-like alveolar development blockage, such as alveolar simplification, reduced alveolar number, and widened alveolar septa. This shows that HAB can significantly reduce the damage of hyperoxia to alveolar development in young mice, thereby improving BPD.

[0104] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0105] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. Use of a metabolite in the preparation of a drug for preventing or treating bronchopulmonary dysplasia, wherein the metabolite has the structural formula 2. The use according to claim 1, characterized in that: Bronchopulmonary dysplasia includes one or more of the following features: (1) Alveolar development blockage; (2) Differentiation disorder of Cdkn1a+ transitional cells into AT1 cells; (3) mitochondrial damage in Cdkn1a+ migratory cells; and (4) Abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ transitional cells.

3. The use according to claim 2, characterized in that: The alveolar development block includes alveolar simplification, alveolar number reduction and alveolar septal widening.

4. The use according to any one of claims 1 to 3, characterized in that: The drug repairs mitochondrial damage in Cdkn1a+ transitional cells.

5. The use according to any one of claims 1 to 3, characterized in that: The drug improves abnormal changes in mitochondrial morphology and distribution in Cdkn1a+ transitional cells.

6. The use according to any one of claims 1 to 3, characterized in that: The drug promotes the differentiation of Cdkn1a+ transitional cells into AT1 cells.

7. The use according to any one of claims 1 to 3, characterized in that: The drug improves alveolar development in bronchopulmonary dysplasia.

8. The use according to claim 7, characterized in that: The drug improves alveolar simplification, reduction in alveolar number and widening of alveolar septa.

9. The use according to any one of claims 1 to 3 and 8, characterized in that: The medicine comprises an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the metabolite.

10. The use according to claim 9, characterized in that: The auxiliary materials include at least one of a filler, a binder, a wetting agent, a disintegrant, a lubricant, a solubilizer, a pH regulator and a flavoring agent.

11. The use according to any one of claims 1 to 3, 8 and 10, characterized in that: The dosage form of the drug includes injection, oral solution, pill, powder, paste, tablet, granule, powder or capsule.

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