Benzyl o-hydroxybenzoate and its pharmaceutical composition and use

Abstract

The present invention belongs to the field of biomedicine, and discloses a novel structural compound FN as shown in formula (I) obtained by separation from the natural drug Solidago asiatica and its pharmaceutically acceptable salt, a preparation method thereof, a pharmaceutical composition containing the compound, and the use of the compound in the preparation of drugs for inflammation, fibrosis-related diseases and acute lung injury. The active natural product FN or its pharmaceutically acceptable salt involved in the present invention has a simple preparation method and has obvious anti-inflammatory, anti-fibrosis and pharmacodynamic activity for the treatment of acute lung injury.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a method for preparing a novel structural compound FN or a pharmaceutically acceptable salt thereof isolated from a natural drug Solidago asiatica, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and applications thereof in diseases related to inflammation, fibrosis and acute lung injury. Background Art

[0002] Natural medicines are an important source of modern medicinal compounds. Solidago decurren is a plant of the genus Solidago in the Asteraceae family, mainly produced in East China, Central South, Southwest China, Shaanxi, Taiwan and other regions of my country. Solidago decurren is a medicinal plant with a wide range of applications. It has the effects of dispelling wind and heat, detoxifying and reducing swelling. It is mainly used in the treatment of wind-heat colds, headaches, sore throats, and lung heat coughs. Modern pharmacological studies have shown that Solidago decurren has antibacterial, diuretic, expectorant and antiasthmatic effects. So far, there are few reports on the chemical composition and pharmacological activity of Solidago decurren. Literature reports that its main chemical components include flavonoids, saponins, benzyl benzoate, phenylpropionic acid, etc. FN (Formula I) is a new structure benzyl benzoate natural product discovered by this research group in the study of the chemical composition of Solidago decurren. The results of pharmacological experiments showed that FN has significant anti-inflammatory, anti-fibrotic and therapeutic effects on acute lung injury, and is an active natural product with in-depth research value. Relevant literature search shows that the structure of this compound and related pharmacological activity research have not been reported so far.

[0003] Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a class of o-hydroxybenzoic acid benzyl ester compounds, and a pharmaceutical composition and use thereof.

[0005] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0006] The first aspect of the technical solution of the present invention is to provide a natural product FN as shown in formula (I) and a pharmaceutically acceptable salt thereof.

[0007]

[0008] In this study, a new structure of benzyl benzoate natural product FN was isolated from the medicinal plant Solidago asiatica for the first time, and its structural formula was determined to be formula (I) by spectral analysis.

[0009] The compounds of the present invention include compounds represented by formula (I) and pharmaceutically acceptable salts thereof.

[0010] The second aspect of the technical solution of the present invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0011] The pharmaceutical composition of the present invention is characterized in that the composition comprises a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0012] The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to prepare suitable application forms or dosage forms that can be used as medicines.

[0013] The compound of the present invention or the pharmaceutical composition containing it can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, subcutaneous, intraperitoneal, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc., preferably oral administration.

[0014] The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0015] The compound of the present invention can be made into common preparations, or can be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0016] In order to prepare the unit dosage form into tablets, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, white clay, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, ganpo, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants , such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, tristearate, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0017] In order to make the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, Gelucire, kaolin, talc, etc.; binders, such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.

[0018] In order to prepare the administration unit as a suppository, various carriers known in the art can be widely used, such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, enzymes of higher alcohols, gelatin, semi-synthetic glycerol enzymes, and the like.

[0019] In order to prepare the dosing unit into capsules, the active ingredient is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient can also be prepared into microcapsules, suspended in an aqueous medium to form a suspension, or can be loaded into a hard capsule or prepared into an injection for use.

[0020] For example, the composition of the present invention is made into an injection preparation, such as a solution, a suspension solution, an emulsion, or a freeze-dried powder injection. This preparation can be aqueous or non-aqueous, and can contain one and / or more pharmacodynamically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent can be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol, polyoxyethylene sorbitol fatty acid enzyme, etc. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose, or glycerol can be added to the injection preparation. In addition, conventional cosolvents, buffers, pH regulators, etc. can also be added. These adjuvants are commonly used in the art.

[0021] In addition, if necessary, colorants, preservatives, perfumes, flavoring agents, sweeteners or other materials may be added to the pharmaceutical preparations.

[0022] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0023] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, etc., so the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the compounds of the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of effective drugs contained in the final preparation of the pharmaceutical composition of the present invention to achieve the requirements of its therapeutically effective amount, and complete the purpose of preventing and treating inflammation, fibrosis-related diseases and acute lung injury of the present invention.

[0024] Usually for patients weighing about 75 kg, the daily dose of the compound of the present invention is 0.001 mg / kg body weight to 400 mg / kg body weight, preferably 1 mg / kg body weight to 200 mg / kg body weight. The above dosage can be administered in a single dosage form or divided into several, such as two, three or four dosage forms, which is limited by the clinical experience of the doctor administering the drug and the dosage regimen. The compound or composition of the present invention can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs.

[0025] The third aspect of the technical solution of the present invention is to provide the use of the compound FN described in formula (I) and its pharmacodynamically acceptable salt and its pharmaceutical composition in the preparation of drugs for treating and / or preventing inflammation, fibrosis-related diseases and acute lung injury.

[0026] The inflammatory diseases include arthritis, nephritis, tracheitis, rhinitis, and pharyngitis. The fibrotic diseases include pulmonary fibrosis and liver fibrosis.

[0027] In order to achieve the purpose of the present invention, the present invention relates to the use of benzyl o-hydroxybenzoate FN and its pharmacologically acceptable salt and pharmaceutical salt thereof, pharmaceutical carrier and / or excipient, and pharmaceutical composition thereof in inflammation, fibrotic diseases and acute lung injury.

[0028] Inflammation is the basic symptom of inflammatory diseases such as arthritis, nephritis, tracheitis, rhinitis, pharyngitis, etc., and anti-inflammatory treatment is a necessary means of clinical treatment. FN has a significant inhibitory effect on croton oil-induced mouse otitis. The inhibition rates of 25, 50, 100, and 200 mg / Kg body weight were 44.0%, 49.6%, 55.4%, and 72.0%, respectively. The inhibition rate at the same dose (50 mg / Kg) was significantly better than that of the positive control drug (26.0%).

[0029] Anti-fibrosis can effectively slow down the progression of diseases such as pulmonary fibrosis and liver fibrosis. Hydroxyproline production in mouse lung fibroblasts (NIH3T3) induced by TGF-β1 was used to simulate tissue fibrosis in vitro. The increase in collagen fibers in the tissue reflected its degree of fibrosis. FN at doses of 10μM and 20μM can significantly reduce the increase in hydroxyproline production in NIH3T3 cells induced by TGF-β1, showing a significant anti-fibrotic effect.

[0030] Acute lung injury is caused by direct or indirect factors that damage alveolar epithelial cells and capillary endothelial cells, leading to acute hypoxic respiratory insufficiency. The present invention uses LPS tracheal instillation to induce the preparation of a mouse acute lung injury (ALI) model. FN can significantly reduce the total white blood cell, neutrophil, and lymphocyte count levels in the BALF of ALI mice at doses of 7.5, 15.0, and 30 mg / kg; at doses of 12.5, 25.0, 50, and 100 mg / kg, it can significantly increase the blood pO2, SaO2, and pH levels of the abdominal aorta of ALI mice, and reduce the blood pCO2 level. After administration of each dose of FN, mice did not show toxic side effects, while 4 mice died in the positive drug indomethacin (15.0 mg / kg) group, and mice in the dexamethasone group (12.5 and 15.0 mg / kg) were thin and listless, showing obvious toxic side effects.

[0031] The fourth aspect of the technical solution of the present invention is to provide a method for preparing the natural product represented by formula (I).

[0032] In order to achieve the above-mentioned purpose of the present invention, the present invention separates and prepares a new structure natural product FN from the medicinal plant Solidago asiatica, and the molecular formula is C 16 H 16 O5, named 2-hydroxybenzoic acid 2,6-dimethoxyphenyl methyl ester. It is characterized in that the separation and preparation steps are as follows:

[0033] Step 1: grind the whole herb of Solidago asiatica, soak it in hot water for 1 hour, filter it while hot, remove the filtrate, and continue to extract the remaining residue with 75% ethanol reflux twice, each time for 2-3 hours, combine the extracts, and concentrate under reduced pressure to obtain an ethanol extract.

[0034] Step 2: Add an appropriate amount of water to the ethanol extract to prepare a suspension, extract with an equal volume of dichloromethane for 3 times, combine the extracts, and concentrate under reduced pressure to obtain a dichloromethane extract.

[0035] Step 3: Separate the dichloromethane extract by silica gel column chromatography, and gradient elute with petroleum ether / ethyl acetate 4:1, 2:1, 1:2. Collect the 4:1 eluate, and concentrate under reduced pressure to obtain a separation fraction rich in FN.

[0036] Step 4: The FN-rich separation segment is further subjected to silica gel column chromatography, eluted with dichloromethane, and the eluate is collected, concentrated under reduced pressure, and dried to obtain a natural product FN sample (compound with the structure of formula (I)).

[0037] Compared with the prior art, the beneficial technical effects of the present invention are as follows: (1) the present invention is the first to separate and identify a natural product FN of benzyl o-hydroxybenzoate with a new structure from the medicinal plant Solidago asiatica; (2) the present invention is the first to discover and confirm that the compound has strong anti-inflammatory, anti-fibrosis and anti-acute lung injury activities, and shows relatively small toxic side effects; (3) the compound of the present invention has a high content in plants, the raw materials are easily available, and the extraction and separation methods are simple and easy, and has good economic value and application prospects. DETAILED DESCRIPTION

[0038] The following examples further illustrate the present invention, but the present invention is not limited to these examples. The test materials used in the following examples, except for the prepared compounds of the present invention, can be purchased from commercial channels.

[0039] Example 1: Extraction, separation and structural identification of compound FN

[0040] 5.0 kg of the whole herb of Solidago striata was crushed, soaked in hot water for 1 hour, filtered while hot, and the filtrate was removed. The remaining residue was further extracted with 75% ethanol for 2 times, each time for 2-3 hours. The extracts were combined and concentrated under reduced pressure to obtain an ethanol extract; the ethanol extract was suspended in an appropriate amount of water, extracted with an equal volume of dichloromethane for 3 times, the extracts were combined, and concentrated under reduced pressure to obtain a dichloromethane extract; the dichloromethane extract was separated by silica gel column chromatography, and gradient eluted with petroleum ether / ethyl acetate (4:1, 2:1, 1:2), and the 4:1 eluate was collected and concentrated under reduced pressure. The obtained sample segment was further subjected to silica gel column chromatography, eluted with dichloromethane, and the eluate was concentrated under reduced pressure and dried to obtain 1500 mg of the natural compound (FN) of formula (Ⅰ).

[0041] 2-Hydroxybenzoic acid 2,6-dimethoxyphenyl methyl ester (FN): white powder.1 H NMR (500MHz, acetone-d6), δ10.90 (1H, s), 7.59 (1H, d, J = 7.6Hz), 7.40 (1H, J = 8.4Hz), 7.35 (1H, t, J = 7.8 Hz),7.06(1H,d,J=8.3Hz),7.02(1H,t,J=7.5Hz),6.61(1H,d,J=8.4Hz),6.57(1H,d,J=8.3Hz),5.42(2H,s),3.89(3H,s),3.87(3H,s). 13 HRESI m / z:289.1068[M+H] + ,cald for C 16 H 16 O5,289.1071[M+H] + .

[0042] Pharmacological experiments:

[0043] Experimental Example 1: Inhibitory effect of FN on croton oil-induced otitis in mice

[0044] Experimental method: 18-22g Kunming male mice were randomly divided into model group, FN group (25, 50, 100, 200mg / kg) group and positive control group (indomethacin 50mg / kg), 10 mice in each group. Drugs were administered by intraperitoneal injection, and the model group was given an equal volume of normal saline. 30min after administration, 50μl of 2% croton oil was applied to the front and back sides of the left ear of the mice, and the mice were killed by dislocation 4h later. The two ears were cut along the auricle baseline, and round ear pieces were punched at the same part of the two ears with a puncher with a diameter of 8mm. The ears were weighed with a precision balance, and the ear swelling degree (ear swelling degree = left ear piece weight - right ear piece weight) and ear swelling inhibition rate [ear swelling inhibition rate (%) = (average ear swelling degree of model group - ear swelling degree of drug administration group) / average ear swelling degree of model group × 100%].

[0045] Experimental results:

[0046] The experimental results are shown in Table 1. All doses of FN had significant inhibitory activity on croton oil-induced mouse ear swelling (P < 0.05 or 0.001), and the inhibition rate of 200 mg / Kg was up to 72%, showing a significant dose-dependent relationship. Compared with the positive control drug of the same dose, FN had a stronger activity in inhibiting croton oil-induced mouse otitis.

[0047] Table 1. Effect of FN on croton oil-induced otitis in mice (Mean±SD, n=10)

[0048]

[0049] Note: Compared with the model control group, *p<0.05, ***p<0.001.

[0050] Experimental Example 2: Inhibitory effect of FN on hydroxyproline production in TGF-β1-induced mouse lung fibroblasts (NIH3T3)

[0051] Hydroxyproline (HYP) is a unique amino acid in tissue collagen, accounting for about 13% of the total collagen amino acids, and can be used as an important indicator of connective tissue collagen metabolism. When tissue fibrosis occurs, the main component that increases in the tissue is collagen fibers, and HYP is unique to collagen. Therefore, the content of HYP in the tissue can reflect its degree of fibrosis. This experiment observed the effect of FN on the production of HYP in mouse lung fibroblasts (NIH3T3) induced by TGF-β1, and its inhibitory effect on pulmonary fibrosis.

[0052] Experimental methods:

[0053] NIH3T3 cells in the logarithmic growth phase were taken and cultured at 1×10 5 10 cells / well were inoculated in a 24-well plate and cultured in an incubator at 37°C and 5% CO2 for 24 hours. After that, the medium was replaced with serum-free DMEM medium and cultured for another 6 hours. Except for the blank control group, TGF-β1 was added to each well to a final concentration of 10 ng / ml. After cultured for another 24 hours, the cell supernatant was collected and assayed according to the instructions of the hydroxyproline detection kit. After the supernatant was collected, the medium containing MTT was added to the well plate and incubated in an incubator at 37°C and 5% CO2 for 4 hours. The cell proliferation was determined by the MTT method.

[0054] Experimental results:

[0055] The experimental results are shown in Table 2. Compared with the blank control group, the model group and each FN administration group had no significant effect on cell proliferation, indicating that the model stimulation and FN had no toxic inhibitory effect on the cells. Compared with the model group, FN can significantly reduce the increase in hydroxyproline production in NIH3T3 cells induced by TGF-β1, indicating that FN can inhibit fibrosis of NIH3T3 cells to a certain extent.

[0056] Table 2. Effect of FN on hydroxyproline production in NIH3T3 cells induced by TGF-β1 (Mean±SD, n=3)

[0057]

[0058] Note: Compared with the blank control group, ## p<0.01; compared with the model control group, ***p<0.001.

[0059] Experimental Example 3: Effect of FN on Acute Lung Injury (ALI)

[0060] (1) Effect of FN on LPS-induced lung inflammation in ALI mice

[0061] Experimental methods:

[0062] Male Kunming mice weighing 18-22g were randomly divided into blank group, model group, FN group (7.5, 15, 30mg / kg) and positive control group (indomethacin 15mg / kg; dexamethasone, 15mg / kg), with 8 mice in each group. Each group of animals was intraperitoneally injected according to the dose setting, once a day, for 4 consecutive days, and the blank group and model group were given an equal volume of normal saline. One hour after administration on the third day, the animals were anesthetized by intraperitoneal injection of 0.6% sodium pentobarbital 0.1ml / 10g, and 50μL LPS (2.4mg / ml) solution was slowly dripped into the trachea, and the blank control group was given an equal volume of normal saline. The animals were killed by dislocation 1h after administration on the fourth day, and bronchoalveolar lavage fluid (BALF) was obtained for white blood cell classification and counting on a five-differentiation blood cell analyzer.

[0063] Experimental results:

[0064] As shown in Table 3, compared with the blank group, the total white blood cells, neutrophils, lymphocytes and monocytes / macrophages in the BALF of ALI model mice were significantly increased, and the administration of FN, indomethacin and dexamethasone significantly reduced the total white blood cell, neutrophil and lymphocyte counts in the BALF of model mice. Four mice died in the positive drug indomethacin group, and the mice in the dexamethasone group were thin and listless, showing obvious toxic and side effects. In comparison, the mice in each dose of FN group were in good condition and did not show obvious toxic and side effects.

[0065] Table 3. Effect of FN on the leukocyte differential count in BALF of ALI mice (Mean±SD)

[0066]

[0067] Note: Compared with the blank control group, ## p<0.01, ### p<0.001; compared with the model control group, **p<0.01, ***p<0.001 (2) Effect of FN on arterial blood gas in LPS-induced ALI mice

[0068] Experimental methods:

[0069] Male Kunming mice weighing 18-22g were randomly divided into blank group, model group, FN group (12.5, 25, 50, 100mg / kg) group and positive control group (dexamethasone 12.5mg / kg), with 8 mice in each group. Animals in each group were intraperitoneally injected according to the dose setting, once a day for 4 consecutive days, and the blank group and model group were given an equal volume of normal saline. One hour after administration on the third day, the animals were intraperitoneally injected with 0.6% sodium pentobarbital 0.1ml / 10g for anesthesia, and 50μL LPS (2.4mg / ml) solution was slowly dripped into the trachea, and the blank control group was given an equal volume of normal saline. One hour after administration on the fourth day, the animals were intraperitoneally injected with 1.0% sodium pentobarbital (0.1ml / 10g) for anesthesia, and blood was collected from the abdominal aorta, and blood gas analysis was immediately performed on a blood gas analyzer (pHOx, NOVA).

[0070] Experimental results:

[0071] As shown in Table 4, compared with the blank group, the arterial oxygen partial pressure (pO2), oxygen saturation (SaO2) and blood pH value (pH) of ALI model mice were significantly reduced, and the blood carbon dioxide partial pressure (pCO2) was significantly increased. After administration of various doses of FN and dexamethasone, the pO2, SaO2 and pH values ​​of the abdominal aorta blood of model mice were significantly increased, and the blood pCO2 level was reduced. The mice in the FN dose groups were in good condition and did not show obvious toxic and side effects. The mice in the dexamethasone group were thin and listless, showing obvious toxic and side effects.

[0072] Table 4. Effect of FN on abdominal aorta blood gas in ALI mice (Mean±SD, n=8)

[0073]

[0074] Note: Compared with the blank group, ### p<0.001; compared with the model group, *p<0.05, **p<0.01, ***p<0.001

[0075] In summary, the results of the study show that FN has significant anti-inflammatory activity; it can significantly inhibit the occurrence of TGF-β1-induced fibrosis; it improves arterial blood gas damage in mice with acute lung injury and reduces the lung inflammatory cell count in mice with acute lung injury; it shows significant anti-inflammatory, anti-fibrotic and anti-acute lung injury pharmacodynamic activity. Moreover, compared with positive drugs, FN has not been found to have any toxic side effects, showing a significant low-toxicity advantage. FN has a very broad prospect for development and application.

Claims

1. A benzyl o-hydroxybenzoate compound FN and a pharmaceutically acceptable salt thereof as shown in formula (I):

2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition is selected from tablets, capsules, pills and injections.

4. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition is selected from sustained-release preparations and / or controlled-release preparations.

5. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition is selected from a microparticle drug delivery system.

6. Use of the compound according to claim 1 and its pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing inflammation, fibrosis-related diseases and / or acute lung injury.

7. Use of the pharmaceutical composition according to claim 2 in the preparation of drugs for treating and / or preventing inflammation, fibrosis-related diseases and / or acute lung injury.

8. The use according to any one of claims 6 or 7, characterized in that The inflammation and fibrosis related diseases include: arthritis, nephritis, tracheitis, pulmonary fibrosis, and liver fibrosis.

Images