Composition for preventing or treating pulmonary fibrosis containing taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as an active ingredient

Abstract

The present invention relates to a composition for preventing or treating pulmonary fibrosis, which contains a pharma- tically acceptable salt of taurodeoxycholic acid as an active ingredient.Specifically, it has been confirmed that administration of a pharma- tically acceptable salt of taurodeoxycholic acid reduces pulmonary fibrosis and the expression of pulmonary fibrosis-related factors in both an animal model of idiopathic pulmonary fibrosis and a cell model of pulmonary fibrosis.Therefore, the taurodeoxycholic acid or its pharma-tically acceptable salt can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis.

Description

[Technical field]

[0001] The present invention relates to a composition for preventing or treating pulmonary fibrosis, which comprises taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient. [Background technology]

[0002] It is known that inflammation is caused by PAMPs (pathogen-associated molecular patterns) triggered by infection with pathogens and DAMPs (damage-associated molecular patterns) triggered by non-infectious damage in tissues. It is known that the failure to control the defense and inflammatory responses in the body involving immune cells, blood vessels, and inflammatory mediators triggered by PAMPs leads to inflammatory diseases. Meanwhile, steroids, NSAIDs (nonsteroidal anti-inflammatory drugs), antibody therapeutics, JAK inhibitors, etc. are currently prescribed as treatments for inflammatory diseases, but steroid drugs are only prescribed for short periods due to systemic side effects, and NSAIDs have not shown sufficient efficacy in the clinical stage. In addition, antibody therapeutics can be administered in a relatively short period of time and for a long period of time, but there are problems such as side effects at the injection site, gradual decrease in effectiveness due to the production of neutralizing antibodies in the body, and high patient costs. On the other hand, JAK inhibitors have excellent anti-inflammatory effects, but there is a risk of increasing serious infections, and clinical trials have confirmed side effects on the cardiovascular system and a risk of carcinogenesis. Intractable inflammatory diseases have a high recurrence rate and require long-term administration for treatment. However, the therapeutic agents developed to date do not satisfy these unmet market demands, and so there is a need to develop new therapeutic agents.

[0003] Formation of the NLRP3 inflammasome, which plays a central role in inflammatory responses in the body, is a key component of the innate immune system that mediates the activation of caspase-1 and the secretion of the inflammatory cytokines IL-1β / IL-18 in response to microbial infection and cell damage. Inflammasomes are cytoplasmic multiprotein oligomers of the innate immune system responsible for activating inflammatory responses. Inflammasome activation promotes the proteolysis, maturation and secretion of the inflammatory cytokines pro-IL-1β and pro-IL-18 into active IL-1β and IL-18, as well as the caspase-1-mediated cleavage of gasdermin-D. Dysregulation of inflammasome activation can lead to a variety of diseases, including cancer, metabolic disorders, degenerative diseases and inflammatory diseases. Specifically, abnormal activation of the NLRP3 inflammasome is associated with the development and aggravation of various inflammatory diseases, including ulcerative colitis, gout, multiple sclerosis, arthritis, sepsis and inflammatory neurological diseases. The NLRP3 inflammasome is also activated by pathogen-associated molecular patterns (PAMPs), such as viruses and bacteria, and danger-associated molecular patterns (DAMPs), such as calcium influx, mitochondrial reactive oxygen species, and extracellular APT.

[0004] On the other hand, the P2X7 receptor is an ion channel receptor composed of a complex belonging to the P2Xn purinergic receptor family. P2X7 stimulation promotes the extracellular release of potassium ions and the rapid influx of calcium and sodium ions into cells. In pathological conditions caused by the occurrence of inflammatory factors both in and out of the body, the concentration of extracellular ATP increases significantly, activating the P2X7 receptor. This activation causes the outflow of potassium ions and an imbalance of intracellular ions, promoting the NLRP3 inflammasome. Furthermore, the activation of the NLRP3 inflammasome leads to the activation of pro-IL-1β / pro-IL-18, which promotes cell death and aggravates the inflammatory response in the surrounding tissues. The P2X7 receptor, which plays an important role in the progression of inflammatory responses, is widely expressed in various immune cells, epithelial cells, nerve cells, etc. P2X7 receptor signaling activates both the canonical and non-canonical pathways of NLRP3 activation, so ATP-P2X7 interaction is crucial for NLRP3 inflammasome activation. For example, high concentrations of ATP released from necrotic cells act as inflammatory DAMPs and bind to the P2X7 receptor to activate the NLRP3 inflammasome.

[0005] Development of new drugs targeting the NLRP3 inflammasome, a key regulator of inflammatory responses, has been attempted many times in the past. In recent years, it has been found that inflammasomes are activated through both canonical and non-canonical pathways involving procaspases, gasdermin D, ASC, NLR proteins, AIM2, IF116, pyrin, etc. Furthermore, it has been found that dysregulation of inflammasomes in these processes causes various diseases. As a result, since 2010, active development of drugs targeting proteins involved in inflammasome-related signaling has been carried out. Representative inflammasome-modulating drugs that have been developed include P2X7 receptor antagonists, NLRP3 inhibitors, and caspase-1 inhibitors. Specifically, P2X7 antagonists have been developed by global pharmaceutical companies such as Pfizer, AstraZeneca, and Janssen, and are indicated for rheumatoid arthritis, Crohn's disease, depression, etc. However, most of these development efforts have been discontinued because insufficient efficacy was confirmed in clinical trials. Development of caspase-1 inhibitors was discontinued in 2020 due to failure to meet efficacy evaluation targets and safety concerns in clinical trials, leaving no global development pipeline for this class of drug. NLRP3 inhibitors are being developed by venture companies such as OLATEC, IMFLAZOME, IFM THERAPETICS, NODTHERA, and AC Immune, and are indicated for osteoarthritis, systolic heart failure, Parkinson's disease, inflammatory bowel disease, Alzheimer's disease, etc. As mentioned above, most of these inflammasome regulators in pharmaceutical development have not been successful in clinical trials. The underlying reason is that these drugs only target specific drug standards and cannot effectively inhibit the various inflammatory pathways that activate the NLRP3 inflammasome. Specifically, currently known inflammasome modulators, such as P2X7 receptor antagonists, NLRP3 inhibitors, and caspase-1 inhibitors, selectively inhibit inflammatory cytokines such as IL-1β and IL-18 caused by inflammation, but have the limitation that they cannot inhibit TNF-α, an inflammatory cytokine that is activated at the onset of inflammation.This indicates a fundamental limitation of drugs that selectively target only NLRP3 or P2X7, because the pharmacological mechanism that selectively inhibits only the inflammatory activation step is insufficient to inhibit the inflammatory response through various bypass pathways. As a result, there are many reports in clinical practice that patients' drug responsiveness and anti-inflammatory effects to current inflammasome-modulating drugs are not met due to compensatory activation of alternative bypass pathways.

[0006] Furthermore, due to the inherent genetic redundancy and polymorphism of NLRP3 and P2X7, it has become clear that current inflammasome-modulating drugs do not achieve the targeted drug response rate in actual clinical practice. Specifically, it has been found that the NLPR3 inflammasome is present in the homologous NLRP inflammasome family, which has the same protein domain as the NLRP3 inflammasome, and this is the cause of off-target side effects of inflammasome-modulating drugs. P2X7 and NLRP3 proteins are associated with hundreds to thousands of single nucleotide polymorphisms (SNPs), resulting in high genetic diversity among individuals. As a result, there are large individual differences in drug response rates and efficacy, suggesting that new drugs targeting these proteins are unlikely to achieve a wide range of therapeutic effects without individual differences. As mentioned above, currently developed inflammasome-targeting drugs, such as P2X7 receptor antagonists, NLRP3 inhibitors, and caspase-1 inhibitors, have many limitations in achieving the intended clinical effects.

[0007] In an attempt to overcome the limitations of existing inflammasome-targeting drugs, recent efforts have focused on developing therapeutic agents targeting GPCR19, which controls upstream signaling of inflammasomes. Specifically, TUDCA, INT-747 (obeticholic acid, OCA), and INT-777 (S-EMCA) are representative examples. TUDCA is currently undergoing clinical trials for diseases such as type 2 diabetes, ulcerative colitis, and amyotrophic lateral sclerosis (ALS). Similarly, INT-747 is also undergoing clinical trials for diseases such as biliary cirrhosis, nonalcoholic steatohepatitis, and liver cirrhosis. All of these compounds are bile acid derivatives and are being investigated as agonists of GPCR19. In particular, GPCR19 is mainly expressed in immune cells, and selectively induces immune cell-mediated anti-inflammatory effects while minimizing nonspecific side effects on normal cells. This is in contrast to existing anti-inflammatory agents such as steroids and JAK inhibitors, whose drug targets are distributed throughout the body beyond the site of inflammation. As a result, these drugs induce a wide range of systemic reactions, and side effects such as systemic metabolic disorders, increased risk of infection, and increased risk of carcinogenesis have been reported. Considering these factors, therapeutic drugs targeting GPCR19 are expected to have a significant advantage in terms of safety.

[0008] To date, no GPCR19-targeted therapeutic has demonstrated efficacy in clinical trials. One of the most advanced GPCR19-targeted therapeutics failed in phase 3 clinical trials for inflammatory diseases due to insufficient anti-inflammatory effects. In fact, the first therapeutics targeting GPCR19 were developed using artificially overexpressed cell lines without fully investigating the anti-inflammatory mechanism of GPCR19. These drugs were developed through systems that do not accurately reflect the initiation and activation of GPCR19-mediated inflammation in vivo, leading to clinical failure. Therefore, there is still a strong need to develop new drugs with broad anti-inflammatory effects that can effectively inhibit both the initiation and activation of inflammation through GPCR19-targeted therapy.

[0009] Recently, bile acids have emerged as novel compounds being investigated as regulators of GPCR19. Bile acids are amphipathic molecules with both hydrophobic and hydrophilic regions. When examining the biosynthesis of bile acids, cholesterol serves as a precursor that is converted by cytochrome P450 enzymes in the liver to primary bile acids, specifically cholic acid and chenodeoxycholic acid. These primary bile acids are then conjugated with taurine or glycine by hepatocytes, which increases their hydrophilicity as they travel to the intestine, and are converted to secondary bile acids by the intestinal microflora. The secondary bile acids are reabsorbed back to the liver through the enterohepatic circulation and travel via the blood vessels to various tissues where they perform various physiological functions. Specifically, they promote fat digestion through their amphipathic nature, inhibit the overgrowth of harmful intestinal microorganisms through their acidity, and promote the excretion of cholesterol during the enterohepatic circulation process. Secondary bile acids are also known to signal through receptors such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, GPCR19), a G protein-coupled receptor located on the cell membrane. Specifically, bile acids bound to the farnesoid X receptor inhibit gluconeogenesis and lipogenesis genes, inhibiting gluconeogenesis and lipogenesis in the liver. Interaction with G protein-coupled bile acid receptor 1 promotes metabolic activity, promotes insulin secretion, and inhibits cytokine release. In particular, binding to G protein-coupled bile acid receptor 1 also inhibits inflammatory responses, so there has been active research into the treatment of bile acid-related inflammatory and autoimmune diseases in conditions affecting the skin, nervous system, stomach, intestines, liver, and joints.

[0010] Pulmonary fibrosis is defined as the abnormal or excessive accumulation of extracellular matrix, especially fibrillar collagen, and refers to the abnormal accumulation of collagen matrix due to injury or inflammation that alters the structure and function of various tissues. Inflammation is central to the development of fibrosis in the lung, and inflammatory cells, including mast cells, are found in abundance in pulmonary fibrosis.

[0011] Pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lungs. This scar tissue replaces healthy tissue and leads to inflammation, which can be identified as a precursor to fibrosis. This damage to lung tissue can make the lungs stiffer and make it difficult to breathe autonomously.

[0012] Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive, irreversible fibrosing interstitial pneumonia of unknown cause that occurs primarily in older adults. In the United States, 100,000 people have idiopathic pulmonary fibrosis, which carries a poor prognosis with a high risk of death within a few years of diagnosis. Treatment options are limited to supplemental oxygen to halt disease progression and improve symptoms and lung function. The clinical course of IPF includes acute exacerbations that often lead to hospitalization.

[0013] Antifibrotic drugs such as pirfenidone and nintedanib are used in patients with idiopathic pulmonary fibrosis. The pharmacological mechanisms of these drugs are as follows: pirfenidone exhibits antifibrotic effects by inhibiting fibroblast proliferation and collagen synthesis, and nintedanib is a low-molecular-weight tyrosine kinase inhibitor that targets fibroblast growth factor receptors. The main target receptors are platelet-derived growth factor receptors (PDGFRα, β), fibroblast growth factor receptors (FGFR1, 2, 3), and vascular endothelial growth factor receptors (VEGFR1, 2, 3). They are equipped with pathological mechanisms that competitively bind to target receptors and inhibit intracellular signaling processes. These drugs have been proven to be effective in slowing the progression of the disease, but do not fundamentally treat the disease. Specifically, in the case of pirfenidone, more than 10% of users experience side effects such as digestive system (dyspepsia, loss of appetite, nausea, diarrhea, etc.), fatigue, headache, and rash. Additionally, 1-10% of users report side effects such as central nervous system (insomnia, dizziness, drowsiness, etc.), skin problems (photosensitivity, pruritus, etc.), gastrointestinal problems (taste abnormalities, abdominal pain, abdominal distension, etc.), weight loss, elevated liver enzymes, chest pain, joint pain, and weakness. Less than 1% of users report side effects such as angioedema and agranulocytosis. In the case of nintedanib, more than 10% of users experience symptoms such as gastrointestinal abnormalities (diarrhea, vomiting, nausea, abdominal pain), hepatobiliary abnormalities (elevated liver enzymes, elevated alanine aminotransferase (ALT), etc.), metabolic and nutritional abnormalities, and loss of appetite. Additionally, 1-10% of users have experienced hepatic and biliary abnormalities (e.g., drug-induced liver damage, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase (ALKP), elevated gamma-glutamyltransferase (GGT)), vascular abnormalities (e.g., hypertension, bleeding), metabolic and nutritional abnormalities (e.g., weight loss), and nervous system abnormalities (e.g., headaches). Side effects reported in less than 1% of users include gastrointestinal abnormalities (e.g., pancreatitis), hepatic and biliary abnormalities (e.g., hyperbilirubinemia), blood and lymphatic abnormalities (e.g., thrombocytopenia), and skin and subcutaneous tissue abnormalities (hair loss).In addition, drugs currently under development for the treatment of idiopathic pulmonary fibrosis include pentraxin-2, connective tissue growth factor (CTGF) inhibitors, autotaxin inhibitors, PI3 kinase / mTOR inhibitors, and galectin-3 inhibitors. Although many clinical studies have been conducted, there is still no drug that can cure the disease, and in some cases, patients with advanced disease may need to consider lung transplantation. Therefore, there is an urgent need to develop a therapeutic drug that can be effective in treating idiopathic pulmonary fibrosis.

[0014] Furthermore, in the case of pharmaceutical compositions manufactured for the treatment of idiopathic pulmonary fibrosis, including those in the prior art, there is a problem that they only provide partial therapeutic effects or only provide negligible levels of efficacy, resulting in a lack of significance and inability to provide fundamental effects that can delay or treat the onset or progression of pulmonary fibrosis.

[0015] In addition, pharmaceutical compositions developed for the treatment of idiopathic pulmonary fibrosis, including those based on conventional technology, exhibit low biocompatibility due to their chemical composition, have a high incidence of side effects, and pose challenges in large-scale production and quality control in terms of productivity.

[0016] Therefore, the present inventors have endeavored to develop a therapeutic drug that is safe, has no side effects, and shows excellent therapeutic effects against pulmonary fibrosis. As a result, it has been confirmed that administration of a pharma- ceutical acceptable salt of taurodeoxycholic acid reduces the expression of pulmonary fibrosis and pulmonary fibrosis-related factors in an animal model of idiopathic pulmonary fibrosis. The present application was filed by clarifying that the taurodeoxycholic acid or a pharma-ceutical acceptable salt thereof can be used as an active ingredient in a composition for preventing or treating pulmonary fibrosis. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] WO 2019-139956(2019.07.18) [Patent Document 2] WO 2015-189401(2015.12.17) [Patent Document 3] WO 2017-152048(2017.09.08) [Patent Document 4] WO 2019-126089(2019.06.27) [Non-patent literature]

[0018] [Non-Patent Document 1] Won-Il Choi, Current and future treatment for idiopathic pulmonary fibrosis, J Korean Med Assoc. 2021;64(4):256-263 Summary of the Invention [Problem to be solved by the invention]

[0019] An object of the present invention is to provide a composition for preventing, treating or ameliorating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as an active ingredient, and which is highly effective and has few side effects. [Means for solving the problem]

[0020] In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0021] The present invention also provides a functional health food composition for preventing or ameliorating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0022] The present invention also provides a food composition for preventing or ameliorating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0023] The present invention also provides a method for preventing or treating pulmonary fibrosis, which comprises the step of administering taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof to an individual.

[0024] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis.

[0025] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as a health functional food composition for preventing or ameliorating pulmonary fibrosis.

[0026] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis.

[0027] Furthermore, the present invention provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof for the manufacture of a health functional food composition for preventing or ameliorating pulmonary fibrosis. Effect of the Invention

[0028] The present inventors have confirmed that administration of a pharma- tically acceptable salt of taurodeoxycholic acid to an animal model of bleomycin-induced idiopathic pulmonary fibrosis and a cell model of pulmonary fibrosis induced by TGF-β reduces the expression of pulmonary fibrosis and pulmonary fibrosis-related factors. Therefore, the taurodeoxycholic acid or a pharma-tically acceptable salt thereof can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a schematic diagram showing a method for preparing an animal model of bleomycin-induced idiopathic pulmonary fibrosis and administering sodium taurodeoxycholate (hereinafter referred to as "HY209"), which is the sodium salt of taurodeoxycholic acid, to the animal model. [Diagram 2]FIG. 1 is a graph confirming changes in body weight after administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis. [Diagram 3] This figure confirms the changes in lung weight observed after HY209 administration in an animal model of bleomycin-induced idiopathic pulmonary fibrosis (*p<0.05 compared to the Natrozole treatment group, #p<0.05 compared to the lung fibrosis group). [Figure 4] Figure 1 confirms the histopathological changes observed after HY209 administration in an animal model of bleomycin-induced idiopathic pulmonary fibrosis (#p<0.05 compared to control group, *p<0.05 compared to natrozole-treated group, **p<0.05 compared to pulmonary fibrosis group). [Diagram 5] This figure confirms the changes in α-SMA expression distribution observed after HY209 administration in an animal model of bleomycin-induced idiopathic pulmonary fibrosis (*p<0.05 compared to the Natrozole treatment group, #p<0.05 compared to the lung fibrosis group). [Figure 6] This figure shows the changes in expression of Col1α1, α-SMA, or PAI-1 after inducing fibrosis in the human lung fibroblast cell line MRC5 with TGF-β and simultaneously treating it with HY209 or TUDCA (*p<0.05 compared to the group treated with TGF-β only; **p<0.01 compared to the group treated with TGF-β only). [Figure 7A] FIG. 1 shows the results of differentiating the human monocyte cell line U937 into macrophages using PMA (phorbol 12-myristate 13-acetate), then inducing an inflammatory response with BzATP (2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate), and measuring the inhibitory effect of HY209 or TUDCA on the production of the inflammatory cytokine IL-1β. [Figure 7B] FIG. 13 shows the results of differentiating U937 cell line into macrophages using PMA (phorbol 12-myristate 13-acetate), then inducing an inflammatory response with Pam2CSK4 (Pam2CysSerLys4), and measuring the inhibitory effect of HY209 or TUDCA on the production of the inflammatory cytokine TNF-α. BEST MODE FOR CARRYING OUT THEINVENTION

[0030] The present invention will now be described in more detail.

[0031] In the present invention, the term "prevention" refers to the act of inhibiting or delaying the occurrence, spread, and recurrence of a disease by administering a composition of the present invention, and the term "treatment" refers to the act of improving or beneficially changing the symptoms of a disease by administering a composition of the present invention.

[0032] In the present invention, the term "administration" means providing a given substance to a patient by any suitable method, and the route of administration of the composition of the present invention may be oral or parenteral administration by any common route that can reach the target tissue. Furthermore, the composition can be administered by any device that allows the active substance to be transferred to the target cells.

[0033] The present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0034] The present invention also provides a method for preventing or treating pulmonary fibrosis, which comprises the step of administering taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof to an individual.

[0035] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis.

[0036] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis.

[0037] In the present invention, the taurodeoxycholic acid is a type of bile acid in the form of taurine-conjugated deoxycholic acid, and has a chemical structure represented by the following formula (1), more specifically, a chemical structure represented by the following formula (2).

[0038] [ka]

[0039] [ka]

[0040] The taurodeoxycholic acid may be isolated from the carcasses of animals such as cows, pigs, sheep, dogs, goats or rabbits, commercially obtained, or synthesized.

[0041] In the present invention, the pulmonary fibrosis refers to the formation or development of excess fibrous connective tissue (fibrosis) in the lungs, and refers to the progression of scarred (fibrotic) tissue. Specifically, pulmonary fibrosis is a chronic disease that causes swelling and scarring of alveolar and interstitial tissues. This scar tissue replaces healthy tissue, causing inflammation, and chronic inflammation can be considered a precursor to fibrosis. Such damage to lung tissue makes the lungs stiff, making it difficult to breathe on one's own.

[0042] Furthermore, the pulmonary fibrosis may specifically refer to, but is not limited to, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, idiopathic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, interstitial pulmonary fibrosis, or diffuse pulmonary fibrosis, and more specifically may refer to, but is not limited to, idiopathic pulmonary fibrosis.

[0043] The pulmonary fibrosis may develop due to various causes, such as micro-damage to the lungs caused by inhalation of fine particles (asbestos, talc, metal dust, particles contained in cigarette smoke, silica dust, etc.). In addition, pulmonary fibrosis may develop as a secondary effect of other diseases (autoimmune diseases, viral or bacterial infections, etc.), and may be induced by certain drugs, such as cytotoxic drugs (bleomycin, busulfan, methotrexate, etc.); antibiotics (nitrofurantoin, sulfasalazine, etc.); antiarrhythmic drugs (amiodarone, tocainide, etc.); anti-inflammatory drugs (gold, penicillamine, etc.); and illegal drugs (narcotics, cocaine, heroin, etc.). In the case of idiopathic pulmonary fibrosis, it may develop due to unknown causes other than those mentioned above.

[0044] In the present invention, the composition can prevent or treat pulmonary fibrosis by reducing the expression of pulmonary fibrosis-associated factors, such as Col1α1, α-SMA or PAI-1.

[0045] In a specific embodiment of the present invention, the present inventors administered a pharma- tically acceptable salt of taurodeoxycholic acid to an animal model of idiopathic pulmonary fibrosis induced by bleomycin, and confirmed a decrease in pulmonary fibrosis and expression of α-SMA, a pulmonary fibrosis-related factor. In addition, administration of a pharma- tically acceptable salt of taurodeoxycholic acid in a pulmonary fibrosis cell model induced by TGF-β reduced expression of Col1α1, α-SMA and PAI-1, which are pulmonary fibrosis-related factors. Therefore, the taurodeoxycholic acid or its pharma- tically acceptable salt can be used as an active ingredient of a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0046] The taurodeoxycholic acid of the present invention includes pharma- ceutically acceptable salts, solvates, hydrates, racemates, or stereoisomers that may be produced therefrom.

[0047] The taurodeoxycholic acid of the present invention can be used in the form of a pharma- ceutically acceptable salt, and salts formed from pharma- ceutically acceptable free acids are useful. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1, These include 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0048] The acid addition salt according to the present invention can be prepared by a conventional method. For example, the taurodeoxycholic acid of the present invention is dissolved in an excess of aqueous acid, and the resulting salt is precipitated with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Furthermore, the mixture can be dried by evaporating the solvent or excess acid, or the precipitated salt can be collected by suction filtration.

[0049] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. In this case, it is pharma- ceutically appropriate to prepare a sodium salt, potassium salt, or calcium salt, and more specifically, in the case of taurodeoxycholic acid, it is appropriate to prepare a sodium salt. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0050] The taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof of the present invention may be included in a therapeutically effective amount and may include a pharma- ceutically acceptable carrier.

[0051] As used herein, an "effective amount" refers to an amount of a compound of the present invention sufficient to slow or minimize the disease or to provide a therapeutic benefit in the treatment or management of the disease.

[0052] The pharma- ceutically acceptable carriers include, for example, carriers for oral administration or parenteral administration. Carriers for oral administration include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Carriers for parenteral administration include water, suitable oils, saline, aqueous glucose, and glycols, etc., and further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. For other pharma-ceutically acceptable carriers, the following literature can be referred to (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

[0053] The pharmaceutical composition of the present invention can be administered to mammals, including humans, via any route, and can be administered orally or parenterally.

[0054] Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal administration. For example, the pharmaceutical composition of the present invention can be prepared into an injection formulation and administered by lightly piercing the skin with a 30-gauge fine needle, or by directly applying or attaching to the skin.

[0055] The pharmaceutical composition of the present invention can be formulated into preparations for oral or parenteral administration depending on the administration route as described above.

[0056] For oral administration, the composition of the present invention can be formulated using methods known in the art, such as powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. For example, oral preparations can be obtained by blending the active ingredient with a solid excipient, then pulverizing, adding suitable auxiliary agents, and processing into a granular mixture to obtain a tablet. Examples of suitable excipients include sugars such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, and maltitol, starches such as corn starch, wheat starch, rice starch, and potato starch, celluloses such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethyl-cellulose, gelatin, and fillers such as polyvinylpyrrolidone. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate can be added as a disintegrant in some cases. Furthermore, the pharmaceutical composition of the present invention may further comprise an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.

[0057] For parenteral administration, the formulations may be formulated in the form of injections, creams, lotions, topical ointments, oils, moisturizers, gels, patches, aerosols, and nasal inhalants by methods known in the art, and are described in all commonly known formulation texts in pharmaceutical chemistry (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour).

[0058] The total dose of the pharmaceutical composition of the present invention can be administered to the patient as a single dose or as multiple doses to the patient through a split treatment protocol. The pharmaceutical composition of the present invention can vary in the amount of active ingredient depending on the symptoms of the disease. Specifically, the total dose of the composition of the present invention can be about 0.01 μg to 1,000 mg per kg of patient body weight per day, more specifically 0.1 μg to 100 mg. However, the dosage of the pharmaceutical composition of the present invention can be determined by a person skilled in the art taking into account various factors such as the patient's age, body weight, health condition, sex, severity of the disease, diet, excretion rate, as well as the route of administration and the number of treatments. The pharmaceutical composition according to the present invention is not particularly limited in dosage form, route of administration, and method of administration as long as it exerts the effects of the present invention.

[0059] In addition, the pharmaceutical composition of the present invention can be administered as a monotherapy or in combination with other therapeutic agents. When administered in combination with other therapeutic agents, the composition of the present invention and the other therapeutic agents can be administered simultaneously, separately, or sequentially. In this case, the other therapeutic agents may be substances that are already known to have a therapeutic or ameliorating effect on pulmonary fibrosis. When the pharmaceutical composition of the present invention is administered in combination with other therapeutic agents, the composition of the present invention and the other therapeutic agents may be formulated in separate containers, or may be formulated together in the same formulation.

[0060] Furthermore, the present invention provides a functional health food composition for preventing or ameliorating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0061] The present invention also provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as a health functional food composition for preventing or ameliorating pulmonary fibrosis.

[0062] Furthermore, the present invention provides use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof for the manufacture of a health functional food composition for preventing or ameliorating pulmonary fibrosis.

[0063] In the present invention, the details of the taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof are the same as those described above, so only the specific composition of the health functional food composition will be described below.

[0064] Meanwhile, the present inventors have confirmed that the administration of a pharma- tically acceptable salt of taurodeoxycholic acid to a bleomycin-induced idiopathic pulmonary fibrosis animal model and a TGF-β-induced pulmonary fibrosis cell model reduces pulmonary fibrosis and the expression of pulmonary fibrosis-related factors. Therefore, the taurodeoxycholic acid or a pharma-tically acceptable salt thereof can be used as an active ingredient of a health functional food composition for preventing or improving pulmonary fibrosis.

[0065] The health functional food composition of the present invention can be prepared in any dosage form selected from the group consisting of powder, granules, pills, tablets, capsules, candies, syrups and beverages, but is not limited thereto.

[0066] The health functional food composition is not particularly limited as long as it is useful for preventing or improving a disease by ingestion. When the health functional food composition of the present invention is used as a food additive, it may be added as it is, or may be used in combination with other foods or food ingredients, and may be used appropriately according to the usual method. The active ingredient may be used appropriately according to its purpose of use (prevention or improvement). Usually, when producing a food or beverage, it is added to the health functional food composition of the present invention in an amount of 15 parts by weight or less, preferably 10 parts by weight or less. However, when taking it for a long period of time for the purpose of health regulation, it may be less than the above range, and since there is no safety problem, the active ingredient may be used in an amount exceeding the above range. There is no particular limit to the type of the food. Examples of foods to which the health functional food composition can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea beverages, alcoholic beverages, and vitamin complexes, and all health foods in the usual sense are included. The health functional food composition of the present invention can also be produced as a food, particularly a functional food.

[0067] The functional food of the present invention includes ingredients that are usually added during food production, such as proteins, carbohydrates, fats, nutrients, and seasonings. For example, when producing a beverage, natural carbohydrates or flavorings can be added as additional ingredients in addition to the active ingredients. The natural carbohydrates are preferably monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g., dextrin, cyclodextrin, etc.), or sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). The flavorings can be natural flavorings (e.g., thaumatin, stevia extract, etc.) or synthetic flavorings (e.g., saccharin, aspartame, etc.). In addition to the health functional food composition, various nutrients, vitamins, electrolytes, seasonings, colorants, pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc. may also be included.

[0068] The present invention will now be described in detail with reference to examples.

[0069] However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

[0070] Example 1: Creation of bleomycin-induced idiopathic pulmonary fibrosis animal model and experimental design

[0071] To investigate the efficacy of taurodeoxycholic acid (TDCA) in pulmonary fibrosis, an animal model of bleomycin-induced idiopathic pulmonary fibrosis was prepared and sodium taurodeoxycholate (hereinafter referred to as "HY209"), the sodium salt of TDCA, was administered to the animal model.

[0072] Specifically, 9-week-old C57B / L6 mice were purchased and allowed to adapt to the environment for one week before the experiment. The experimental animals were kept under conditions of a temperature of 22 ± 2°C, relative humidity of 55 ± 10%, and a 12-hour light-dark cycle. Water was provided ad libitum, and sterilized feed was used, with food available ad libitum.

[0073] Next, as shown in FIG. 1, bleomycin (BLM, Enzo Life Sciences, Cas. No. 9041-93-4) was administered intranasally to the mice at a concentration of 1 mg / mL. The mice were then divided into 7 groups as shown in Table 1 below, and the samples were administered during the fibrotic phase (days 7 to 21) following the inflammatory phase (days 0 to 7). The pulmonary fibrosis group was orally administered a vehicle (0.5% CMC (carboxymethylcellulose) solution) at a dose of 10 mL / kg twice a day, and the experimental group was orally administered HY209 formulated in a 5% CMC solution to a final concentration of 10, 30, or 60 mg / kg twice a day. The comparative group (nintedanib-administered group) was orally administered nintedanib formulated in a vehicle (0.1% Natrosol; hydroxyethylcellulose solution) to a final concentration of 60 mg / kg twice a day. The lung fibrosis group (Natrosol group) compared with the Nintedanib group was orally administered 10 mL / kg of 0.1% Natrosol solution twice a day. The control group was administered saline instead of bleomycin and orally administered 10 mL / kg of vehicle (0.5% CMC (carboxymethylcellulose) solution) twice a day.

[0074] [Table 1]

[0075] <Example 2> Confirmation of body weight change after administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0076] The changes in body weight of each mouse in Example 1 were monitored.

[0077] Specifically, the body weight of each group of mice was measured every day during the experiment.

[0078] As a result, as shown in FIG. 2, no significant difference was observed in the change in body weight between the HY209-administered group and the control group.

[0079] <Example 3> Confirmation of changes in lung weight after administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0080] The change in lung weight of each mouse in Example 1 was confirmed.

[0081] Specifically, the mice in each group were sacrificed after the experiment, and the lungs were excised and weighed.

[0082] As a result, as shown in Figure 3, the lung weights of the bleomycin-induced idiopathic pulmonary fibrosis group and the Natrozole-administered group were significantly increased compared to the control group. Meanwhile, the lung weights of the nintedanib-administered group were significantly decreased compared to the Natrozole-administered group. Furthermore, the lung weights of the HY209 10 mg / kg and HY209 60 mg / kg-administered groups were statistically significantly decreased compared to the pulmonary fibrosis group.

[0083] <Example 4> Confirmation of histopathological changes after administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0084] The pulmonary fibrosis of each of the mice in Example 1 was evaluated.

[0085] Specifically, mice from each group were sacrificed at the end of the experiment, and the lungs were removed. The removed lungs were embedded in paraffin for histopathological evaluation and stained according to the Crossman's trichrome method (Gray P. The Microtomist's Formulary and Guide. Published by Robert E. Krieger Publishing Co.). The histological changes in the lungs were evaluated using the Matsuse modified version of the Ashcroft score (Ashcroft H et al. J Clin Pathol (1988) 41:467-70; Matsuse T et al. Eur Respir J (1999) 13:71-77), as shown in Table 2 below.

[0086] [Table 2]

[0087] As a result, as shown in Figure 4, pulmonary fibrosis was significantly increased in the pulmonary fibrosis group and the Natrozole-administered group compared to the control group. On the other hand, pulmonary fibrosis was significantly reduced in the Nintedanib-administered group compared to the Natrozole-administered group. In addition, pulmonary fibrosis was statistically significantly reduced in the HY209 10 mg / kg and HY209 60 mg / kg administration groups compared to the pulmonary fibrosis group.

[0088] <Example 5> Confirmation of changes in expression of pulmonary fibrosis-related factors after administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0089] The expression distribution of fibrosis-related factors in the lung tissue of each mouse in Example 1 was confirmed.

[0090] Specifically, the mice in each group were sacrificed at the end of the experiment, and the lungs were removed. The lungs were embedded in paraffin for histopathological evaluation, and sections were taken and mounted on slides. The expression distribution of fibrosis-related factor α-SMA in the lung tissue was then evaluated.

[0091] Immunohistochemical analysis of α-SMA was performed using a polyclonal anti-α-SMA antibody. Antigen retrieval was performed using Target retrieval solution pH6 (PT Link modul, DAKO). Slides were reacted with a primary rabbit polyclonal anti-SMA antibody and then with the ImmPRESS detection kit (Autostainer Link48, DAKO). The level of de novo accumulation of de novo α-SMA was assessed using digital image analysis software (Visiopharm®). Results were expressed as percentage (%) of α-SMA area.

[0092] As a result, as shown in Figure 5, the α-SMA area was significantly increased in the pulmonary fibrosis group and the Natrosol-administered group compared to the control group. No significant difference was observed between the pulmonary fibrosis group and the Natrosol-administered group.

[0093] On the other hand, the nintedanib group showed a significant decrease in α-SMA area compared to the pulmonary fibrosis group and the Natrozole group.Also, the HY209 10 mg / kg and HY209 60 mg / kg groups showed a significant decrease in α-SMA area compared to the pulmonary fibrosis group and the Natrozole group.

[0094] <Example 6> Comparison of inhibitory effects of HY209 and TUDCA on the expression of fibrosis-related factors

[0095] To compare the fibrosis-inhibiting abilities of HY209 and TUDCA (tauroursodeoxycholic acid) in pulmonary fibrosis, we measured their ability to inhibit the expression of fibrosis-related factors in human lung fibroblast cell line MRC5 cells treated with TGF-β simultaneously with administration of HY209 or TUDCA by qPCR.

[0096] Specifically, human lung fibroblast cell line MRC5 cells were cultured in a 6-well plate at 2 × 10 cells per well. 5 Cells were seeded at a density of 1000 mM and cultured overnight to allow cell adhesion. The medium was then removed, and the cells were treated with TGF-β1 at a concentration of 5 ng / mL and HY209 or TUDCA at concentrations of 0, 0.1, 1, or 10 μM, cultured for 48 hours, and the cells were harvested. RNA was then extracted from the cells using an RNeasy Mini Kit (QIAGEN), and cDNA was synthesized using Maxime® RT PreMix (LiliF Diagnostic). qPCR measurements were performed using Power SYBR® Green PCR Master Mix (Thermo Scientific) according to the manufacturer's instructions. In addition, primers specific to Col1α1, α-SMA, and PAI-1 were used to confirm their expression, and GAPDH was used as an internal control.

[0097] As a result, as shown in Figure 6, HY209 inhibited the expression of α-SMA and PAI-1 at concentrations of 0.1, 1, and 10 μM, whereas TUDCA showed no inhibitory activity at concentrations of 0.1 and 1 μM, but only at 10 μM. Furthermore, HY209 decreased the expression of Col1α1 at concentrations of 0.1, 1, and 10 μM, whereas TUDCA increased the expression at concentrations of 0.1 and 1 μM.

[0098] The results showed that the inhibitory ability of HY209 on the expression of fibrosis-related factors was significantly superior to that of TUDCA.

[0099] <Example 7> Evaluation of the inflammation inhibitory ability of HY209 and TUDCA

[0100] To evaluate the anti-inflammatory efficacy of HY209 and TUDCA, human monocytic cell line U937 was treated with PMA (phorbol 12-myristate 13-acetate) to induce differentiation into macrophages. Inflammatory responses were then induced using BzATP (2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate) or Pam2CSK4 (Pam2CysSerLys4), and the inhibitory ability of HY209 or TUDCA on the production of inflammatory cytokines IL-1β and TNF-α was measured.

[0101] Specifically, human mononuclear cell line U937 was seeded at a density of 70,000 cells per well in a 96-well plate and cultured in RPMI1640 medium containing 50 nM PMA (phorbol 12-myristate 13-acetate) for 24 hours to induce differentiation into macrophages. Next, the medium was removed from each well, and HY209 or TUDCA was administered at various concentrations (HY209: 1, 0.5, 0.25, 0.125, 0.0625, 0.0312, 0.0156, 0.0078 μM; TUDCA: 1000, 316, 100, 31.6, 10, 3.16, 0.316, 0.1, 0.0316, 0.01, 0.00316 μM) for 12 hours. Then, BzATP (2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate) was added to each well to a final concentration of 300 μM, and the cells were cultured for an additional 12 h. After that, the supernatants were collected and IL-1β levels were measured using an IL-1β ELISA kit (R&D Systems) according to the manufacturer's instructions (Figure 7A).

[0102] In addition, human mononuclear cell line U937 was cultured at 5 × 10 6 The cells were cultured at a density of 50,000 cells per well for 5 hours to induce differentiation into macrophages. The differentiated macrophages were then seeded into a 96-well plate at a density of 50,000 cells per well and cultured for 24 hours to rest. The medium was then replaced with serum-free medium and cultured for 12 hours. The medium was then removed from each well, and the cells were treated with 50 ng / mL Pam2CSK4 (Pam2CysSerLys4) and varying concentrations of HY209 or TUDCA (HY209: 10, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125 μM, TUDCA: 100, 50, 25, 12.5, 6.25, 3.125, 1.562, 0.76 μM) for 4 hours. Thereafter, the supernatants were collected, and TNF-α levels were measured using a TNF-α ELISA kit (R&D Systems) according to the manufacturer's instructions ( Fig. 7B ).

[0103] As a result, as shown in Figures 7A and 7B, HY209 and TUDCA had IC values ​​of 0.044 and 1.496 μM, respectively, for inhibiting IL-1β production. 50 The IC values ​​for TNF-α were 0.36 and 13.1 μM, respectively (Figure 7A). 50 The values ​​were shown (Figure 7B).

[0104] These results suggest that HY209 has an increased IC value for IL-1β compared with TUDCA. 50 value of 34-fold, IC against TNF-α 50 As is clear from the 36-fold lower value, it was confirmed that the compound exhibited significantly superior inflammation inhibitory efficacy.

[0105] In the present invention, it has been confirmed that a pharma- ceutical acceptable salt of taurodeoxycholic acid reduces pulmonary fibrosis and the expression of pulmonary fibrosis-related factors in both an animal model of idiopathic pulmonary fibrosis and a cell model of pulmonary fibrosis. Therefore, the taurodeoxycholic acid or its pharma-ceutical acceptable salt of the present invention can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis.

Claims

1. A pharmaceutical composition for preventing or treating pulmonary fibrosis, comprising taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as an active ingredient.

2. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein the taurodeoxycholic acid is a compound represented by the following formula (2): 【Chemistry 1】

3. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein the pharma- ceutical acceptable salt is a sodium salt.

4. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein the composition reduces the expression of a factor associated with pulmonary fibrosis.

5. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 4, wherein the factor associated with pulmonary fibrosis is COL1α1, α-SMA or PAI-1.

6. 2. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein the pulmonary fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, idiopathic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, interstitial pulmonary fibrosis and diffuse pulmonary fibrosis.

7. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, further comprising one or more pharma- ceutically acceptable carriers.

8. A functional health food composition for preventing or ameliorating pulmonary fibrosis, comprising taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as an active ingredient.

9. A food composition for preventing or ameliorating pulmonary fibrosis, comprising taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as an active ingredient.

10. A method for preventing or treating pulmonary fibrosis, comprising the step of administering taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof to an individual.

11. Use of taurodeoxycholic acid or a pharma- ceutical acceptable salt thereof as a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis.

12. Use of taurodeoxycholic acid or a pharma- ceutically acceptable salt thereof as a health functional food composition for preventing or ameliorating pulmonary fibrosis.

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