Pharmaceutical composition for prevention or treatment of neonatal bronchopulmonary dysplasia, comprising mir-203a-3p as active ingredient

Abstract

The present inventors have confirmed that miR-203a-3p contained in extracellular vesicles derived from mesenchymal stem cells may be used for the treatment of neonatal bronchopulmonary dysplasia through an anti-apoptotic effect and an anti-inflammatory effect of miR-203a-3p. Thus, a pharmaceutical composition according to the present invention may be usefully employed as a medicine and a health functional food for the prevention, mitigation, or treatment of neonatal bronchopulmonary dysplasia.

Description

Pharmaceutical composition for the prevention or treatment of neonatal bronchopulmonary dysplasia comprising miR-203a-3p as an active ingredient

[0001] One example of the present invention is,

[0002] The present invention relates to a pharmaceutical composition, pharmaceutical preparation, and health functional food for the prevention or treatment of neonatal bronchopulmonary dysplasia, comprising miR-203a-3p as an active ingredient, for the prevention or improvement of neonatal bronchopulmonary dysplasia.

[0003] Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease (CLD) of the neonatal period first described by Northway et al. in 1967, and refers to the appearance of characteristic radiological and pathological abnormalities in the lungs along with symptoms of respiratory failure such as persistent tachypnea, respiratory distress, chest retraction, hypoxemia, and hypercapnia in premature infants receiving mechanical ventilation and oxygen therapy.

[0004] With the recent advancements in neonatal medical care, the survival rate of extremely low birth weight infants weighing less than 1,500 g has increased, and consequently, the incidence of bronchopulmonary dysplasia, one of the major chronic complications affecting them, is also rapidly increasing.

[0005] Premature infants with bronchopulmonary dysplasia often require longer neonatal intensive care, such as mechanical ventilation in the neonatal intensive care unit, or die in the short term. However, even after surviving and being discharged, they frequently suffer from long-term sequelae such as growth retardation, neurodevelopmental delays, and frequent respiratory infections, so prevention and treatment are very important.

[0006] However, despite the significant impact bronchopulmonary dysplasia has on the clinical course of premature infants, there is currently no definitive preventive or therapeutic method available, leaving it as one of the most intractable diseases in premature infants.

[0007]

[0008] All cells must exchange information with their surrounding environment and other cells for survival, and to facilitate this information exchange, cells secrete various substances outside the cell, such as cytokines, hormones, and soluble factors like neurotransmitters. Recently, extracellular vesicles, also known as exosomes, have been attracting attention as a new type of intercellular information exchange mechanism.

[0009] Extracellular vesicles (EVs) refer to microscopic particles ranging in size from several nanometers to several micrometers that are secreted from cells or cells into which genetic material has been introduced, and are surrounded by a lipid bilayer. Recently, various studies have been conducted on the important functions of extracellular vesicles.

[0010] The secretion of extracellular vesicles is a phenomenon that is evolutionarily conserved across all biological kingdoms, ranging from bacteria and archaea to eukaryotes.

[0011] In particular, extracellular vesicles containing DNA, RNA, functional proteins, and antigens are utilized as a new mode of cell communication. Extracellular vesicles are known to contain specific genetic material and bioactive factors depending on the properties and state of the cell from which they originate. Since extracellular vesicles are fundamentally derived from cells, they are biocompatible unlike other nanoparticles. Furthermore, because they can encapsulate or label drugs or biologically active ingredients internally or on their surface, there are ongoing attempts to utilize them as raw materials for drug delivery systems, cosmetics, and pharmaceuticals.

[0012]

[0013] Accordingly, the researchers confirmed that miR-203a-3p contained in extracellular vesicles derived from mesenchymal stem cells can be used to treat neonatal bronchopulmonary dysplasia through anti-apoptotic and / or anti-inflammatory effects, and completed the present invention after research.

[0014] Accordingly, the present invention

[0015] The purpose is to provide a pharmaceutical composition for the prevention or treatment of bronchopulmonary dysplasia (BPD) in newborns, comprising miR-203a-3p as an active ingredient.

[0016]

[0017] In addition, the present invention

[0018] The purpose is to provide a pharmaceutical preparation for the prevention or treatment of bronchopulmonary dysplasia (BPD) comprising the above-mentioned pharmaceutical composition.

[0019]

[0020] In addition, the present invention

[0021] The purpose is to provide a health functional food for the prevention or improvement of bronchopulmonary dysplasia (BPD) comprising the above pharmaceutical composition.

[0022]

[0023] In addition, the present invention

[0024] The purpose is to provide miR-203a-3p for the prevention or treatment of bronchopulmonary dysplasia (BPD) in newborns.

[0025]

[0026] In addition, the present invention

[0027] The purpose is to provide a method for the prevention or treatment of bronchopulmonary dysplasia (BPD) of newborns, comprising the step of administering miR-203a-3p to an individual in need thereof.

[0028] To achieve the above objective, the present invention

[0029] The present invention provides a pharmaceutical composition for the prevention or treatment of bronchopulmonary dysplasia (BPD) comprising miR-203a-3p as an active ingredient.

[0030] In one embodiment of the present invention, the miR-203a-3p may be derived from an extracellular vesicle.

[0031] In another embodiment of the present invention, the extracellular vesicle may be derived from a stem cell.

[0032] In another embodiment of the present invention, the stem cell may be one or more selected from the group consisting of mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and hematopoietic stem cells.

[0033] In another embodiment of the present invention, the pharmaceutical composition may have an anti-apoptotic effect and / or an anti-inflammatory effect.

[0034] In another embodiment of the present invention, the pharmaceutical composition may reduce the expression level of cPARP (cleaved Poly(ADP-ribose) Polymerase) in lung epithelial cells.

[0035] In another embodiment of the present invention, the pharmaceutical composition may increase the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

[0036] In another embodiment of the present invention, the pharmaceutical composition may reduce the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

[0037]

[0038] In addition, the present invention

[0039] The present invention provides a pharmaceutical preparation for the prevention or treatment of bronchopulmonary dysplasia (BPD) comprising the above pharmaceutical composition.

[0040] In one embodiment of the present invention, the pharmaceutical formulation may reduce the expression level of cPARP (cleaved Poly(ADP-ribose) Polymerase) in lung epithelial cells.

[0041] In another embodiment of the present invention, the pharmaceutical formulation may increase the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

[0042] In another embodiment of the present invention, the pharmaceutical formulation may reduce the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

[0043] In another embodiment of the present invention, the pharmaceutical formulation may further comprise a pharmaceutically acceptable carrier, excipient, or diluent.

[0044] In another embodiment of the present invention, the pharmaceutical formulation may be an oral formulation, an inhaled formulation, a sustained-release formulation, an injectable formulation, an infusion formulation, a spray formulation, a liquid formulation, or a patch formulation.

[0045]

[0046] In addition, the present invention

[0047] The present invention provides a health functional food for the prevention or improvement of bronchopulmonary dysplasia (BPD) comprising the above pharmaceutical composition.

[0048]

[0049] In addition, the present invention

[0050] miR-203a-3p is used for the prevention or treatment of bronchopulmonary dysplasia (BPD) in newborns.

[0051]

[0052] In addition, the present invention

[0053] The present invention provides a method for the prevention or treatment of bronchopulmonary dysplasia (BPD), comprising the step of administering miR-203a-3p to an individual in need thereof.

[0054] The inventors have confirmed that miR-203a-3p contained in extracellular vesicles derived from mesenchymal stem cells can be used to treat neonatal bronchopulmonary dysplasia through anti-apoptotic and anti-inflammatory effects. Therefore, the pharmaceutical composition according to the present invention can be usefully utilized as a medicine and health functional food for preventing, improving, or treating neonatal bronchopulmonary dysplasia.

[0055]

[0056] The effects of the present invention are not limited to those mentioned above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims.

[0057] Figures 1A and 1B show the results of confirming the therapeutic effect of stem cell-derived extracellular vesicles. Specifically, Figure 1A shows the results of quantitatively analyzing the expression levels of the apoptosis markers cPARP and Bcl-2 using Western blot, and Figure 1B shows the results of quantitatively analyzing the expression levels of the inflammatory cytokines IL-1β and IL-6 using real-time PCR.

[0058] Figures 2A and 2B show the results of identifying the active ingredients exhibiting anti-apoptotic and anti-inflammatory effects of stem cell-derived extracellular vesicles. Specifically, Figure 2A shows the results of measuring the expression level of miR-203a-3p after treatment with stem cell-derived extracellular vesicles following treatment with H2O2, and Figure 2B shows the results of measuring the expression level of miR-203a-3p after treatment with stem cell-derived extracellular vesicles following treatment with LPS.

[0059] Figures 3A and 3B show the results of confirming the therapeutic effect of miR-203a-3p as an active ingredient of stem cell-derived extracellular vesicles. Specifically, Figure 3A shows the results of confirming the anti-apoptotic effect of miR-203a-3p after overexpressing miR-203a-3p in lung epithelial cells (A549 cells), and Figure 3B shows the results of confirming the anti-inflammatory effect of miR-203a-3p after overexpressing miR-203a-3p in alveolar macrophages (RAW264.7 cells).

[0060] The present invention will be described in detail below.

[0061] The present invention

[0062] The present invention provides a pharmaceutical composition for the prevention or treatment of bronchopulmonary dysplasia (BPD) comprising miR-203a-3p as an active ingredient.

[0063] The term "miR-203a-3p" as used herein refers to a type of microRNA, a non-coding RNA molecule that regulates gene expression within a cell. MicroRNA is a small RNA composed of about 22 nucleotides that regulates gene expression by binding to the 3' untranslated region (3'UTR) of a target mRNA and inhibiting or inducing degradation of the mRNA.

[0064] "203a" indicates the order in which the microRNA was discovered and the characteristics of its sequence. MicroRNAs with the same number may exist in multiple variant forms, and "a" refers to one of those variants.

[0065] "3p" indicates the directionality of the strand from which the microRNA originated. MicroRNA separates into two strands (5p and 3p) at the precursor (pre-miRNA) stage, each of which can have different biological functions. "3p" means that the microRNA originated from the 3' strand of the precursor, which is involved in regulating gene expression by binding to specific target mRNAs.

[0066] The term “bronchopulmonary dysplasia (BPD)” as used in this specification refers to a chronic respiratory disease (CLD) of the neonatal period first described by Northway et al. in 1967, which describes the appearance of characteristic radiological and pathological abnormalities in the lungs along with symptoms of respiratory failure such as persistent tachypnea, respiratory distress, chest retraction, hypoxemia, and hypercapnia in premature infants receiving mechanical ventilation and oxygen therapy.

[0067] With the recent advancements in neonatal medical care, the survival rate of extremely low birth weight infants weighing less than 1,500 g has increased, and consequently, the incidence of bronchopulmonary dysplasia, one of the major chronic complications affecting them, is also rapidly increasing.

[0068] Premature infants with bronchopulmonary dysplasia often require longer neonatal intensive care, such as mechanical ventilation in the neonatal intensive care unit, or die in the short term. However, even after surviving and being discharged, they frequently suffer from long-term sequelae such as growth retardation, neurodevelopmental delays, and frequent respiratory infections, so prevention and treatment are very important.

[0069] However, despite the significant impact bronchopulmonary dysplasia has on the clinical course of premature infants, there is still no definitive preventive or therapeutic method, leaving it as one of the most intractable diseases in premature infants.

[0070] As used herein, the term "prevention" refers to any act of suppressing symptoms of bronchopulmonary dysplasia (BPD) in an individual or delaying its onset by administering a pharmaceutical composition according to the present invention.

[0071] As used herein, the term "treatment" refers to any act in which symptoms of bronchopulmonary dysplasia (BPD) in an individual are improved or beneficially altered by the administration of a pharmaceutical composition according to the present invention. The intended therapeutic effects include preventing the onset or recurrence of the disease, alleviating symptoms, reducing all direct or indirect pathological consequences associated with the disease, preventing metastasis, reducing the rate of disease progression, alleviating or temporarily resolving the disease state, and improving the disease state or prognosis. For the purposes of the present invention, the above treatment may be interpreted to include all acts of improving said symptoms by administering the pharmaceutical composition of the present invention to a patient with the onset of the disease, but is not specifically limited thereto.

[0072] As used herein, the term "administration" means introducing a pharmaceutical composition of the present invention to a subject by any appropriate method, by providing a composition of the present invention to the subject. The route of administration may be administered via various oral or parenteral routes as long as it can reach the target tissue.

[0073] The pharmaceutical composition of the present invention may be appropriately administered to an individual according to the conventional methods, routes of administration, and dosages used in the art, depending on the purpose or need. Examples of routes of administration may include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and nasal administration, and parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0074] In addition, an appropriate dosage and number of administrations may be selected according to methods known in the art, and the amount and number of administrations of the pharmaceutical composition of the present invention actually administered may be appropriately determined by various factors such as the type of symptom to be treated, the route of administration, gender, health status, diet, age and weight of the individual, and the severity of the disease.

[0075] As used herein, the term "individual" refers to a subject requiring treatment for a disease, and more specifically, to all animals including humans who are likely to develop or have already developed the disease. It may refer to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle, but is not limited thereto.

[0076] Additionally, the above pharmaceutical composition may be provided as a pharmaceutical composition or pharmaceutical preparation comprising an active ingredient alone or comprising one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0077] Specifically, the term “pharmaceuticalally acceptable carrier” as used herein refers to a material commonly used in formulations and may be a colloidal suspension, powder, saline solution, lipid, liposome, microsphere, or nano-spherical particle. It may also include, but is not limited to, saline solution, sterile water, Ringer’s solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, etc., and may further include other conventional additives such as antioxidants, buffers, etc., as needed. These may form a complex with or be associated with a transport means and may be transported in vivo using a transport system known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption-enhancing substances, or fatty acids.

[0078] Additionally, the term “pharmaceuticalally acceptable excipient” as used herein means any substance that is used as a carrier or medium for delivering a pharmaceutical composition according to the present invention, or is added to a formulation to improve handling or storage, or to facilitate the manufacture of a formulation in dosage units into articles such as capsules or tablets suitable for oral administration. Excipients may include, but are not limited to, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, lubricants, fragrances, surfactants, and inclusion compounds.

[0079] When the above pharmaceutical composition is formulated, it may be prepared using excipients or diluents such as commonly used lubricants, sweeteners, flavorings, emulsifiers, suspending agents, preservatives, fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Regarding suitable pharmaceutically acceptable carriers and formulations, each component may be preferably formulated using the methods disclosed in Remington’s literature.

[0080] Solid dosage forms for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the above composition. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

[0081] Liquid formulations for oral administration include suspensions, liquid formulations, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as humectants, sweeteners, flavorings, and preservatives, may be included.

[0082] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, witepsol, macrogol, tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used, and when manufactured in the form of ophthalmic preparations, known excipients or diluents may be used.

[0083] In addition, the above pharmaceutical composition may be administered alone or in combination with other therapeutic agents. That is, the above pharmaceutical composition may be administered in conjunction with a known composition or other agent having a preventive or therapeutic effect on the said disease, and may be administered simultaneously, separately, or sequentially, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art.

[0084] The above pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, the method of administration may be selected as external application to the skin or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intra-arterial injection, intramedullary injection, intracardiac injection, intrathecal injection, transdermal injection, nasal injection, enteral injection, local injection, sublingual injection, rectal injection, or thoracic injection.

[0085] The above pharmaceutical composition is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the type and severity of the patient's disease, the patient's age, gender, condition, body weight, absorption of the active ingredient into the body, the drug's activity, inactivation rate and excretion rate, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. Additionally, the dosage may vary depending on the patient's condition and body weight, the degree of disease, the drug form, route of administration, and time, but can be appropriately selected by a person skilled in the art.

[0086] Specifically, the above pharmaceutical composition may be administered at a dose of 0.001 to 1000 mg / kg / day, more specifically at a dose of 0.1 to 100 mg / kg / day. The administration may be administered once a day or divided into several doses. For example, it may be administered every other day or once a week. However, since the dosage may be increased or decreased depending on the route of administration, severity of obesity, gender, body weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0087]

[0088] In one embodiment of the present invention, the miR-203a-3p may be derived from an extracellular vesicle.

[0089] As used in this specification, the term "Extracellular Vesicle (EV)" refers to a substance surrounded by a lipid bilayer, consisting of particles ranging in size from several nanometers to several micrometers, secreted by a cell or a cell into which genetic material has been introduced. It refers to a vesicle composed of a nano-sized double-layered lipid structure secreted by a cell, specifically natural phospholipids composed of cholesterol, sphingolipids, glycerophospholipids, and ceramide. Recently, various studies have been conducted on the important functions of extracellular vesicles.

[0090] The secretion of extracellular vesicles is an evolutionarily conserved phenomenon across all biological kingdoms, ranging from bacteria and archaea to eukaryotes. In particular, extracellular vesicles containing DNA, RNA, functional proteins, and antigens serve as a novel mode of cell communication. Extracellular vesicles are known to contain specific genetic material and bioactive factors depending on the properties and state of the cell from which they originate. Furthermore, because extracellular vesicles are fundamentally derived from cells, they are biocompatible unlike other nanoparticles. Additionally, continuous efforts are being made to utilize them as raw materials for drug delivery systems, cosmetics, and pharmaceuticals, as they can encapsulate or label drugs or biologically active ingredients on their interior or surface.

[0091] However, development is facing difficulties due to uneconomical productivity (high costs and low yields) and the lack of efficient therapeutic loading technology. Furthermore, the difficulty in diversifying the administration routes of extracellular vesicles and the inability to ensure the stability and safety of the substance, particularly when administered orally, are pointed out as major challenges in development.

[0092] Delivery vehicles such as viruses, lipid nanoparticles, and virus-like particles have been developed for gene therapy. However, existing virus-based delivery vehicles suffer from side effects, such as reduced efficacy due to immune responses to various viruses; lipid nanoparticles, being synthetic materials, present problems regarding immune responses upon repeated administration; and naked gene delivery is limited in its use as a therapeutic agent due to its very low delivery efficiency.

[0093] In contrast, extracellular vesicles possess a stable structure and a higher target delivery rate than conventional drug delivery systems. Therefore, they are gaining attention as next-generation drug delivery systems by loading proteins or other substances intended for delivery to target cells onto the surface or inner membranes of extracellular vesicles.

[0094]

[0095] In another embodiment of the present invention, the extracellular vesicle may be derived from a stem cell.

[0096] As used herein, the term "stem cell" refers to an undifferentiated cell possessing the ability to self-renewal and differentiate into various cell types. Stem cells are broadly classified into embryonic stem cells and adult stem cells; embryonic stem cells possess pluripotency, meaning they can differentiate into all cell types, while adult stem cells possess limited differentiation ability, involved in the regeneration of specific tissues or organs. Stem cells play a crucial role in life science research and medicine, including tissue regeneration, damage repair, and disease treatment. In particular, stem cells are widely utilized in the fields of cell therapy and regenerative medicine, and are attracting attention as an innovative technology that offers the potential to treat various diseases.

[0097] Extracellular vesicles derived from stem cells play an important role in the treatment of intractable lung diseases such as bronchopulmonary dysplasia (BPD). Mesenchymal stem cells possess anti-inflammatory and antioxidant effects, and these properties are transmitted through extracellular vesicles to induce inhibition of apoptosis and reduction of inflammatory responses in lung epithelial cells (A549) and alveolar macrophages (RAW264.7). In particular, miRNA (miR-203a-3p) contained in extracellular vesicles derived from mesenchymal stem cells plays a key role in inhibiting lung cell apoptosis induced by hydrogen peroxide (H2O2) and inflammatory responses induced by lipopolysaccharide (LPS), and in this field of technology, stem cells function as an important source mediating these therapeutic effects.

[0098]

[0099] In another embodiment of the present invention, the stem cell may be one or more selected from the group consisting of mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and hematopoietic stem cells.

[0100] As used herein, the term "Mesenchymal Stem Cell" refers to a type of adult stem cell that originates primarily from sources such as bone marrow, adipose tissue, and umbilical cord blood, and possesses the ability to differentiate into various tissues. Mesenchymal stem cells can differentiate into mesodermal cells, such as bone, cartilage, and fat, and are widely utilized in the fields of regenerative medicine and cell therapy due to their anti-inflammatory and immunomodulatory capabilities. Along with their self-renewal ability, mesenchymal stem cells play an important role in the treatment of various diseases due to their characteristics of repairing damaged tissues and regulating inflammatory responses. In particular, mesenchymal stem cells are suitable for transplantation therapy due to their low immune rejection rate and possess significant potential as therapeutic agents for tissue regeneration and damage repair.

[0101] As used herein, the term "Embryonic Stem Cell" refers to a pluripotent stem cell derived from an early embryo (blastocyst stage) that possesses the ability to differentiate into all cell types. Embryonic stem cells possess self-renewal and infinite proliferation capabilities, enabling them to form various tissues and organs. Due to these characteristics, embryonic stem cells are widely utilized in regenerative medicine, cell therapy, drug development, and disease modeling research. In particular, embryonic stem cells have the potential to be differentiated into specific cell types to repair damaged tissues or treat diseases.

[0102] As used herein, the term "Induced Pluripotent Stem Cell (iPSC)" refers to a cell that has been reprogrammed into a pluripotent stem cell by introducing specific genes (e.g., Oct4, Sox2, Klf4, c-Myc) into an adult cell. Induced pluripotent stem cells have the ability to differentiate into all cell types, similar to embryonic stem cells, and also possess the ability to self-renewal. Since induced pluripotent stem cells can be generated using a patient's somatic cells, they have the advantage of a low risk of immune rejection and minimal ethical controversy. Due to these characteristics, induced pluripotent stem cells play an important role in the fields of regenerative medicine, drug screening, disease modeling, and cell therapy.

[0103] As used herein, the term "hematopoietic stem cell" refers to a stem cell derived from bone marrow, peripheral blood, or umbilical cord blood that has the ability to differentiate into various immune cells, including blood cells. Hematopoietic stem cells possess self-renewal capabilities and play a role in generating all blood components, such as red blood cells, white blood cells, and platelets. Due to these characteristics, hematopoietic stem cells are widely used in the treatment of blood diseases such as leukemia, lymphoma, and aplastic anemia, and are utilized as a key source for cell therapies such as bone marrow transplantation and umbilical cord blood transplantation.

[0104]

[0105] In another embodiment of the present invention, the pharmaceutical composition may have an anti-apoptotic effect and / or an anti-inflammatory effect.

[0106]

[0107] In another embodiment of the present invention, the pharmaceutical composition may reduce the expression level of cPARP (cleaved Poly(ADP-ribose) Polymerase) in lung epithelial cells.

[0108] As used herein, the term "cPARP (cleaved Poly (ADP-ribose) Polymerase)" refers to a protein used as an indicator of apoptosis, specifically the form of Poly (ADP-ribose) Polymerase (PARP) that has been cleaved by caspases. Although PARP is an enzyme that plays a crucial role in DNA damage repair, it becomes inactivated when cleaved by caspase-3 and caspase-7 during the process of apoptosis. This cleaved form, cPARP, serves as a key molecular marker indicating that a cell is following a programmed apoptotic pathway. Therefore, increased expression of cPARP signifies the activation of apoptosis and is used to assess the degree of apoptosis in various disease models.

[0109]

[0110] In another embodiment of the present invention, the pharmaceutical composition may increase the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

[0111] As used herein, the term "Bcl-2 (B-cell lymphoma 2)" refers to an anti-apoptotic protein that plays a role in promoting cell survival and inhibiting apoptosis. Bcl-2 is located on the outer membrane of mitochondria and regulates programmed apoptotic pathways within the cell. This protein inhibits the release of death-inducing factors, such as cytochrome c, by regulating mitochondrial membrane permeability in response to intracellular stress signals. Bcl-2 is often overexpressed in cancer cells, increasing resistance to apoptosis, which contributes to cancer survival and treatment resistance. Therefore, Bcl-2 is an important target for research on apoptosis regulation and the development of anticancer drugs.

[0112]

[0113] In another embodiment of the present invention, the pharmaceutical composition may reduce the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

[0114] As used herein, the term "IL-1β (Interleukin-1beta)" refers to a major cytokine that induces inflammatory responses and plays a significant role in the immune system. IL-1β is primarily produced by macrophages and monocytes and is activated in response to pathogen infection, tissue damage, or inflammatory stimuli. IL-1β recruits immune cells to the site of inflammation and mediates inflammatory responses such as fever, increased vascular permeability, and tissue damage repair. However, excessive IL-1β expression can lead to chronic inflammation, autoimmune diseases, and tissue damage. Therefore, IL-1β is an important target for understanding the pathological mechanisms of inflammatory diseases and for developing therapeutic agents.

[0115] As used herein, the term "IL-6 (Interleukin-6)" refers to a multifunctional cytokine that plays a crucial role in inflammatory responses, immune regulation, and tissue damage repair. IL-6 is primarily secreted by macrophages, T cells, B cells, and fibroblasts, and it activates inflammatory responses in the event of infection or tissue damage. In acute inflammatory responses, IL-6 induces the production of acute-phase proteins such as C-reactive protein (CRP), and in chronic inflammatory states, it can lead to pathological conditions such as autoimmune diseases. Additionally, IL-6 possesses anti-inflammatory effects and plays a role in maintaining the balance of inflammatory responses. As such, IL-6 plays an important role in both normal immune responses and disease states and is being studied as a therapeutic target for various diseases.

[0116]

[0117] In addition, the present invention

[0118] The present invention provides a pharmaceutical preparation for the prevention or treatment of bronchopulmonary dysplasia (BPD) comprising the above pharmaceutical composition.

[0119] The terms used in this pharmaceutical formulation are consistent with the terms described in the above pharmaceutical composition.

[0120] In one embodiment of the present invention, the pharmaceutical formulation may reduce the expression level of cPARP (cleaved Poly(ADP-ribose) Polymerase) in lung epithelial cells.

[0121] In another embodiment of the present invention, the pharmaceutical formulation may increase the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

[0122] In another embodiment of the present invention, the pharmaceutical formulation may reduce the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

[0123] In another embodiment of the present invention, the pharmaceutical formulation may further comprise a pharmaceutically acceptable carrier, excipient, or diluent.

[0124] In another embodiment of the present invention, the pharmaceutical formulation may be an oral formulation, an inhaled formulation, a sustained-release formulation, an injectable formulation, an infusion formulation, a spray formulation, a liquid formulation, or a patch formulation.

[0125] As used herein, the term "Oral Formulation" refers to a pharmaceutical formulation designed to be ingested orally and absorbed through the gastrointestinal tract. Oral formulations are the most widely used method of drug delivery, characterized by ease of administration and high patient compliance. Oral formulations are provided in various forms, such as tablets, capsules, granules, powders, and syrups, and are designed with consideration for the stability and bioavailability of the drug. Since oral formulations involve the absorption of the drug in the digestive tract and metabolization in the liver, various factors affecting the dosage and absorption rate must be considered.

[0126] As used herein, the term "inhalation formulation" refers to a pharmaceutical formulation designed to deliver a drug directly to the lungs through the respiratory system. Inhalation formulations are designed to allow the drug to reach the lungs directly to act locally or be absorbed into the systemic circulation. Inhalation formulations are primarily used to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) and are available in various forms, such as dry powder inhalers, metered-dose inhalers, and nebulizers. Inhalation formulations have the advantage of delivering drugs to lung tissue at high concentrations, resulting in rapid therapeutic effects and minimized systemic side effects.

[0127] As used herein, the term "Sustained-Release Formulation" refers to a pharmaceutical formulation designed to release a drug slowly within the body. Such formulations are intended to maintain a constant blood concentration by controlling the drug's release rate, reduce the frequency of administration, and sustain the drug's effects over a long period. Sustained-release formulations are designed to release the drug gradually in the gastrointestinal tract or activate it at specific time intervals, and are available in various forms such as tablets, capsules, and implants. These formulations have the advantage of increasing patient convenience and minimizing side effects while maximizing therapeutic effects.

[0128] As used herein, the term "Injection Formulation" refers to a pharmaceutical formulation intended for direct administration into body tissues or organs, such as subcutaneous, intramuscular, or intravenous, and is provided as a solution, suspension, emulsion, or a solid sterile preparation to be dissolved or suspended in a solvent at use. Since the drug is delivered directly into the body, the injection formulation can exhibit rapid absorption and immediate therapeutic effects, and is particularly suitable for patients in emergency situations or those for whom oral administration is difficult. This formulation offers the advantages of ensuring drug stability, maximizing bioavailability, and enabling precise dosage control.

[0129] As used herein, the term “Infusion Formulation” refers to a pharmaceutical formulation designed to deliver a drug into the body at a constant rate and administered intravenously, subcutaneously, or via other routes. Infusion formulations are designed to deliver the drug slowly into the bloodstream to maintain a long-term therapeutic effect and are used for the treatment of acute and chronic diseases. They also include pharmaceutical formulations designed to be inserted into the body through the urethra, anus, vagina, etc., and to release their therapeutic effect after dissolving due to body heat or secretions. Infusion formulations are generally provided in liquid form and are designed to maximize the stability and bioavailability of the drug.

[0130] As used herein, the term "spray formulation" refers to a pharmaceutical formulation designed to apply a drug internally or topically by spraying it in the form of a fine mist using a device. Spray formulations are designed to ensure that the drug is evenly dispersed and effectively delivered to specific areas, and are primarily used for localized areas such as the respiratory tract, skin, and mucous membranes. Formulations that utilize a device to spray the drug as a mist are included, and are designed to deliver the drug directly to the lungs, nose, skin, etc., to exert a therapeutic effect. Spray formulations are provided in liquid form and may contain appropriate solvents and additives to maximize drug stability and delivery efficiency.

[0131] As used herein, the term "Liquid Formulation" refers to a pharmaceutical form in which a drug is provided in a liquid form, meaning a formulation containing an active ingredient in liquid form. Liquid formulations are provided by dissolving or suspending a drug in a solvent such as water, alcohol, or oil, and can be used in various ways, such as oral administration, topical application, injection, or inhalation. Liquid formulations have a rapid absorption rate and are easy to administer, making them suitable for patients who have difficulty swallowing solid formulations, such as children or the elderly. Additionally, additives or stabilizers may be included to maintain drug stability and maximize bioavailability.

[0132] As used herein, the term "Patch Formulation" refers to a formulation designed to provide a continuous therapeutic effect when applied to the skin. Patch formulations have the advantage of a lower risk of side effects, such as gastrointestinal or liver damage associated with oral medications, and can be administered to patients for whom oral administration is difficult. Furthermore, because they are absorbed directly into the bloodstream through the skin without undergoing hepatic metabolism, they can produce the same therapeutic effect without side effects at lower doses compared to oral formulations. Patch formulations are primarily used in the treatment of chronic diseases, pain management, and hormone therapy, and various polymer-based technologies are applied to control drug concentration and release rates.

[0133]

[0134] In addition, the present invention

[0135] The present invention provides a health functional food for the prevention or improvement of bronchopulmonary dysplasia (BPD) comprising the above pharmaceutical composition.

[0136] The terms used in this health functional food are consistent with the terms described in the above pharmaceutical composition.

[0137] As used in this specification, the term "improvement" may refer to any action that at least reduces parameters related to the condition being treated, such as the severity of symptoms. In this case, the health functional food may be used for the prevention or improvement of the disease, either simultaneously with or separately from a therapeutic agent, either before or after the onset of the disease.

[0138] The health functional food defined in the present invention may be a health functional food that has sufficiently established functionality and safety for the human body, newly defined through the Health Functional Foods Act revised in 2008, and is listed in the regulations on the recognition of functional ingredients for health functional foods stipulated in KFDA Notice No. 2008-72.

[0139] In the above-mentioned health functional food, the active ingredient may be added directly to the food or used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient may be appropriately determined according to its purpose of use (for prevention or improvement). Generally, the active ingredient constituting the composition according to the present invention may be included in an amount of 0.01 to 15 weight%, preferably 0.2 to 10 weight% of the total food weight, and when manufactured as a beverage, it may be included in a ratio of 0.1 to 30 g, preferably 0.2 to 5 g, based on 100 mL, and the entire beverage may be composed of natural ingredients. However, in the case of long-term consumption for the purpose of health control and hygiene, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.

[0140] The health functional food according to the present invention may be formulated into a formulation of a conventional health functional food known in the art. The health functional food may further include one or more of a carrier, an excipient, a diluent, and an additive, and may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, infusions, liquids, suspensions, emulsions, syrups, extracts, gums, teas, jellies, or beverages.

[0141] Foods to which compounds according to one aspect can be added include various types of food, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, health functional foods, etc.

[0142] As the above-mentioned food-grade acceptable carrier or additive, any carrier or additive known in the relevant art to be available for use in the preparation of the formulation to be prepared may be used. It may also include foods used as animal feed.

[0143] Specific examples of the above carrier, excipient, diluent, and additive may be at least one selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0144] In addition to containing the above-mentioned active ingredient, the above-mentioned health functional food may contain other ingredients as essential components without special restrictions. For example, it may contain various flavorings or natural carbohydrates as additional ingredients, similar to ordinary beverages.

[0145] Examples of the natural carbohydrates described above may be monosaccharides, e.g., glucose, fructose, etc.; disaccharides, e.g., maltose, sucrose, etc.; polysaccharides, e.g., dextrin, cyclodextrin, etc., and conventional sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc. As flavoring agents other than those described above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) may be advantageously used. The proportion of the natural carbohydrates may be appropriately determined by the choice of a person skilled in the art.

[0146] In addition to the above, a health functional food according to one aspect may contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, it may contain fruit pulp for the manufacture of natural fruit juices, fruit juice beverages, and vegetable beverages. In addition, the above health functional food composition may further include food additives, and unless otherwise stipulated, suitability as a "food additive" may be determined according to the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety. These ingredients may be used independently or in combination, and the proportion of such additives may also be appropriately selected by a person skilled in the art.

[0147] In addition, the health functional food of the present invention may include additional ingredients that are commonly used in food compositions to improve odor, taste, visual appearance, etc. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu). In addition, it may include amino acids such as lysine, tryptophan, cysteine, and valine. In addition, food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dihydroacetate, etc.), disinfectants (bleaching powder and high-grade bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), etc.), coloring agents (tar dyes, etc.), colorants (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (sizing agents), coating agents, gum bases, antifoaming agents, solvents, and improvers may be added. The above additives may be selected according to the type of food and used in appropriate amounts.

[0148] When the health functional food of the present invention is used as a food additive, it may be added as is or used together with other foods or food ingredients, and may be used appropriately according to conventional methods.

[0149] In the health functional food of the present invention, the content of the pharmaceutical composition of the present invention is not particularly limited and may be varied depending on the condition of the subject to administration, the specific type of disease, the degree of progression, etc. If necessary, it may also be included in the total content of the food.

[0150] In one aspect, the above-mentioned health functional food may further include a health functional food for the prevention or improvement of the relevant disease.

[0151] The above-mentioned health functional food may be provided in combination with a conventionally known health functional food for the prevention or improvement of the relevant disease or a newly developed health functional food for the prevention or improvement of the relevant disease.

[0152]

[0153] If the above-mentioned health functional food further includes a health functional food for the prevention or improvement of the relevant disease, it is important that an amount is mixed such that the maximum effect can be obtained with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

[0154] In addition, in one aspect, the health functional food may be consumed alone or in combination with a health functional food for the prevention or improvement of the relevant disease. The health functional food may be consumed in conjunction with a known composition or other health functional food having an effect of preventing or improving the relevant disease, and may be consumed simultaneously, separately, or sequentially, and may be consumed as a single or multiple times. It is important to consume an amount that obtains maximum effect with a minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art.

[0155]

[0156] In addition, the present invention

[0157] miR-203a-3p is used for the prevention or treatment of bronchopulmonary dysplasia (BPD) in newborns.

[0158]

[0159] In addition, the present invention

[0160] The present invention provides a method for the prevention or treatment of bronchopulmonary dysplasia (BPD), comprising the step of administering miR-203a-3p to an individual in need thereof.

[0161]

[0162] To aid in understanding the present invention, it will be explained in more detail below through examples. However, the following examples are merely illustrative for explaining the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the technical field to which the invention belongs.

[0163]

[0164] [Example]

[0165] Example 1. Experimental Method

[0166] (1) Method for constructing an in vitro model

[0167] An in vitro model of pulmonary cell death in bronchopulmonary dysplasia was constructed by inducing pulmonary cell death in lung epithelial cells (A549 cells) by exposing them to 75 µM hydrogen peroxide (H2O2) for 24 hours.

[0168] In addition, an in vitro model of pulmonary inflammation of bronchopulmonary dysplasia was constructed by inducing pulmonary inflammation activation in alveolar macrophages (RAW264.7 cells) by exposing them to 100 ng / ml of LPS (lipopolysaccharide) for 24 hours.

[0169] (2) Timing and concentration of treatment with stem cell-derived extracellular vesicles

[0170] Stem cell-derived extracellular vesicles were administered to an in vitro model of lung apoptosis or lung inflammation at 0 hours and 3 hours (total 2 times), 5 x 10 7 0.1ml of particles were treated.

[0171] (3) Analysis method

[0172] 1) Method for analyzing anti-apoptotic effects

[0173] The expression levels of the cell death markers cPARP (cleaved Poly (ADP-ribose) Polymerase) and Bcl-2 (B-cell lymphoma 2) in protein samples obtained by lysing lung epithelial cells (A549 cells) after harvesting were quantitatively analyzed using Western blot.

[0174] 2) Method for analyzing anti-inflammatory effects

[0175] After harvesting alveolar macrophages (RAW264.7 cells), the expression levels of the inflammatory cytokines IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in samples from which RNA and cDNA were synthesized were quantitatively analyzed using real-time PCR.

[0176] (4) miR-203a-3p overexpression method

[0177] Intracellular miR-203a-3p was overexpressed by transfecting cells with mimetic miRNA miR-203a-3p using lipofectamine. The expression levels of apoptosis markers (cPARP and Bcl-2) and inflammatory cytokines (IL-1β and IL-6) were quantitatively analyzed in lung epithelial cells (A549 cells) and alveolar macrophages (RAW264.7 cells) 24 hours after induction of apoptosis and inflammation, respectively.

[0178]

[0179] Example 2. Experimental Results

[0180] 2-1. Confirmation of Therapeutic Effects of Stem Cell-Derived Extracellular Vesicles

[0181] (1) Confirmation of anti-apoptotic effect

[0182] As a result of confirming the anti-apoptotic effect of stem cell-derived extracellular vesicles, as shown in Figure 1A, it was confirmed that apoptosis was significantly induced in the group treated with H2O2 (H2O2(+), Exosome(-)) by showing an increase in cPARP and a decrease in Bcl-2 compared to the untreated group (H2O2(-), Exosome(-)). In addition, it was confirmed that the degree of apoptosis induced by H2O2 was significantly reduced by treatment with stem cell-derived extracellular vesicles by showing a decrease in cPARP and an increase in Bcl-2 in the group treated with stem cell-derived extracellular vesicles (H2O2(+), Exosome(+)).

[0183] (2) Confirmation of anti-inflammatory effect

[0184] As a result of confirming the anti-apoptotic effect of stem cell-derived extracellular vesicles, as shown in Figure 1B, IL-1β and IL-6 increased in the group treated with LPS (LPS) compared to the untreated group (None), but IL-1β and IL-6 increased by LPS were found to decrease in the group treated with LPS and stem cell-derived extracellular vesicles (LPS + Exosome).

[0185] This result indicates that stem cell-derived extracellular vesicles have an inhibitory effect on the inflammatory response in alveolar macrophages (RAW264.7 cells).

[0186]

[0187] 2-2. Identification of active ingredients exhibiting therapeutic effects in stem cell-derived extracellular vesicles

[0188] To identify the active ingredients exhibiting anti-apoptotic and anti-inflammatory effects of stem cell-derived extracellular vesicles, the expression level of miR-203a-3p was measured after treatment with H2O2 or LPS and subsequent treatment with stem cell-derived extracellular vesicles.

[0189] As a result, as shown in Figure 2A, the expression level of miR-203a-3p decreased in the in vitro lung cell death model group (H2O2) compared to the normal control group (None), but was significantly increased in the group treated with stem cell-derived extracellular vesicles (H2O2+ Exosome).

[0190] In addition, as shown in Figure 2B, compared to the normal control group (None), the expression of miR-203a-3p decreased in the in vitro lung inflammation model group (LPS), but it was confirmed to have significantly increased in the group treated with stem cell-derived extracellular vesicles (LPS + Exosome).

[0191] These results indicate that miR-203a-3p within stem cell-derived extracellular vesicles inhibits lung cell apoptosis induced by H2O2 treatment and lung inflammatory responses induced by LPS treatment; thus, it was confirmed that miR-203a-3p is the active ingredient exhibiting anti-apoptotic and anti-inflammatory effects of stem cell-derived extracellular vesicles.

[0192]

[0193] 2-3. Confirmation of the therapeutic effect of miR-203a-3p as an active ingredient of stem cell-derived extracellular vesicles

[0194] In order to confirm the anti-apoptotic and anti-inflammatory effects of miR-203a-3p as an active ingredient of stem cell-derived extracellular vesicles, the following experiments were conducted after overexpressing miR-203a-3p in lung epithelial cells (A549 cells) and alveolar macrophages (RAW264.7 cells).

[0195] (1) Confirmation of anti-apoptotic effect

[0196] As a result of confirming the anti-apoptotic effect of miR-203a-3p, as shown in Figure 3A, it was confirmed that apoptosis was significantly induced in the groups treated with H2O2 (H2O2(+), Control mimic(+), miR-203a-3p mimic(-)) by showing an increase in cPARP (Cleaved PARP) and a decrease in Bcl-2 compared to the untreated control group (H2O2(-), Control mimic(+), miR-203a-3p mimic(-)). In addition, it was confirmed that the degree of apoptosis induced by H2O2 was significantly reduced by the overexpression of miR-203a-3p by showing a decrease in cPARP and an increase in Bcl-2 in the groups overexpressing miR-203a-3p (H2O2(+), Control mimic(-), miR-203a-3p mimic(+)).

[0197] (2) Confirmation of anti-inflammatory effect

[0198] As a result of confirming the anti-inflammatory effect of miR-203a-3p, as shown in Figure 3B, IL-1β and IL-6 increased in the group treated with LPS (LPS) compared to the untreated group (None), but in the group treated with LPS and miR-203a-3p (LPS + miR-203a-3p mimic), IL-1β and IL-6 increased by LPS were found to have decreased.

[0199] This result indicates that overexpressed miR-203a-3p has an effect of suppressing the inflammatory response in alveolar macrophages (RAW264.7 cells).

[0200]

[0201] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for the prevention or treatment of bronchopulmonary dysplasia (BPD), comprising miR-203a-3p as an active ingredient.

2. In Claim 1, A pharmaceutical composition characterized in that the above miR-203a-3p is derived from extracellular vesicles.

3. In Claim 2, A pharmaceutical composition characterized in that the above-mentioned extracellular vesicle is derived from a stem cell.

4. In Claim 3, A pharmaceutical composition characterized in that the above stem cells are one or more selected from the group consisting of mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and hematopoietic stem cells.

5. In Claim 1, The above pharmaceutical composition is characterized by having an anti-apoptotic effect and / or an anti-inflammatory effect.

6. In Claim 1, The above pharmaceutical composition is characterized by reducing the expression level of cPARP (cleaved Poly (ADP-ribose) Polymerase) in lung epithelial cells.

7. In Claim 1, The above pharmaceutical composition is characterized by increasing the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

8. In Claim 1, The above pharmaceutical composition is characterized by reducing the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

9. A pharmaceutical preparation for the prevention or treatment of bronchopulmonary dysplasia (BPD), comprising the pharmaceutical composition of any one of claims 1 to 8.

10. In Claim 9, The above pharmaceutical preparation is characterized by reducing the expression level of cPARP (cleaved Poly (ADP-ribose) Polymerase) in lung epithelial cells.

11. In Claim 9, The above pharmaceutical preparation is characterized by increasing the expression amount of Bcl-2 (B-cell lymphoma 2) in lung epithelial cells.

12. In Claim 9, The above pharmaceutical preparation is characterized by reducing the expression level of one or more selected from the group consisting of IL-1β (Interleukin-1beta) and IL-6 (Interleukin-6) in alveolar macrophages.

13. In Claim 9, The above pharmaceutical formulation is characterized by further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

14. In Claim 9, The above pharmaceutical formulation is characterized by being an oral formulation, an inhaled formulation, a sustained-release formulation, an injectable formulation, an infusion formulation, a spray formulation, a liquid formulation, or a patch formulation.

15. A health functional food for the prevention or improvement of bronchopulmonary dysplasia (BPD), comprising a pharmaceutical composition of any one of claims 1 to 8.

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