Application of compound in preparation of medicine for protecting pulmonary vascular endothelial cells

Abstract

The invention discloses an application of a compound in preparation of a medicine for protecting pulmonary vascular endothelial cells, and relates to the technical field of medicines, the application of the compound in preparation of the medicine for protecting the pulmonary vascular endothelial cells comprises the compound, and the compound is used as an active component of the medicine. The compounds are useful as inhibitors of OSM causing barrier damage to endothelial cells; the compound is used for inhibiting OSM-induced vascular endothelial cell permeability increase in drugs. The compound is used for improving the reduction of vascular epithelial cell membrane electrical impedance caused by OSM in medicines, so that the integrity of a cell barrier is protected; the compound is used for up-regulating vascular endothelial cadherin expression and reducing vascular endothelial permeability in medicines, and repairing vascular endothelial barrier damage caused by OSM. The compound can reverse the reduction of OSM-induced endothelial adhesion connexin and protect the damage of an endothelial barrier, and has a remarkable application prospect in medicines for protecting pulmonary vascular endothelial cells.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to an application of a compound in preparation of a medicine for protecting lung vascular endothelial cells. BACKGROUND

[0002] Vascular endothelial cells are widely distributed in the inner wall of arteries and veins at all levels of the human body, constituting the primary barrier between blood and vascular tissue. They play a crucial role in maintaining vascular permeability, transmitting vascular signals, regulating vascular tension, participating in the hemostasis process, secreting vasoactive substances, and ensuring the supply of oxygen and nutrients to tissues. When the body is infected, invaded by endotoxins, exposed to hypoxic environments, or stimulated by inflammatory cytokines, endothelial cells are damaged. This damage is manifested in the disruption of the barrier function of endothelial cells and the disorder of their normal physiological functions. Endothelial cell damage can trigger a variety of serious pathological conditions, such as atherosclerosis, hypertension, myocardial infarction, pulmonary edema, glomerulonephritis, and cerebrovascular disease. In the respiratory system, infectious acute lung injury and high-altitude pulmonary edema are two common manifestations of pulmonary edema. Infectious acute lung injury is mainly caused by bacterial or viral infection, and high-altitude pulmonary edema is caused by the maladaptation of vascular endothelial cells in the hypoxic environment of high altitude. However, at present, there is no specific drug approved for the clinical treatment of infectious acute lung injury and high-altitude pulmonary edema. Therefore, it is of great significance to discover a compound drug for protecting lung vascular endothelial cells and to accelerate the development of effective drugs for treating lung vascular injury.

[0003] Oncostatin-M (OSM) belongs to the interleukin-6 family and is an inflammatory cytokine with multiple biological activities. It plays a key role in the pathogenesis of various inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, cancer progression and metastasis, and other systems. OSM secreted by activated immune cells in the blood vessel first contacts endothelial cells. Studies have reported that OSM induces brain inflammation by disrupting the integrity of the blood-brain barrier. In the oxygen-induced retinopathy model, OSM reduces retinal neovascularization by activating Müller cells. OSM induces endothelial activation of large vessel endothelial cells and microvascular endothelial cells, as well as APOE*3Leiden.CETP mice, suggesting that OSM may play a role in the initial process of atherosclerotic lesion formation. For the first time, OSM recombinant protein was used to construct an in vivo and in vitro vascular endothelial injury model to find a low-toxicity and high-efficiency OSM inhibitor, which is expected to be used for the development of a medicine for protecting lung vascular endothelial cells; therefore, it is necessary to provide an application of a compound in preparation of a medicine for protecting lung vascular endothelial cells. SUMMARY

[0004] Therefore, the present application aims at the existing defects in the prior art, and the main purpose is to provide an application of a compound in the preparation of a lung vascular endothelial cell protection drug, which can reverse the decrease of OSM-induced endothelial adhesion connection protein (VE-cadherin), reduce the permeability of endothelial cells, and protect the destruction of the endothelial barrier, and has a significant application prospect in the preparation of a lung vascular endothelial cell protection drug.

[0005] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0006] The application of a compound in the preparation of a lung vascular endothelial cell protection drug, wherein the compound has the following structural formula:

[0007] ;

[0008] The drug comprises the compound, and the compound serves as an active ingredient of the drug; and the compound is used as an inhibitor of OSM which causes barrier damage to endothelial cells.

[0009] As a preferred solution, the compound is applied to the active ingredient of the drug for inhibiting the damage of OSM to the endothelial cell barrier, and the use dose is 1-10 μM, and the treatment time of the compound on the endothelial cells is 12 hours.

[0010] As a preferred solution, the compound is applied to the active ingredient of the drug for inhibiting the damage of OSM to the endothelial cell barrier, and the use dose is 10 μM.

[0011] As a preferred solution, the drug further comprises a solvent, an additive and a carrier, the solvent is DMSO, the additive is selected from polyethylene glycol 300, polysorbate 80, sulfobutyl-β-cyclodextrin or corn oil, and the carrier is selected from a natural material or a semi-synthetic material, the natural material comprises gelatin, albumin, starch and chitosan, and the semi-synthetic material comprises hydrogenated soybean phospholipid and polyethylene glycol distearoyl phosphatidyl ethanolamine.

[0012] As a preferred solution, the composition of the solvent and the additive in the drug is as follows: 10% of DMSO plus 40% of polyethylene glycol 300 plus 5% of polysorbate 80 plus 45% of physiological saline; or 10% of DMSO plus 90% of a 20% sulfobutyl-β-cyclodextrin physiological saline solution, or 10% of DMSO plus 90% of corn oil.

[0013] As a preferred solution, the compound in the drug is used for inhibiting the decrease of the expression of VE-cadherin of vascular epithelial cells caused by OSM.

[0014] As a preferred solution, the compound in the drug is used for inhibiting the increase of the permeability of vascular endothelial cells induced by OSM.

[0015] As a preferred solution: the compound is used in medicine to improve the decrease of vascular epithelial cell membrane electrical impedance caused by OSM, thereby protecting the cell barrier integrity.

[0016] As a preferred solution: the compound is used in medicine to up-regulate vascular endothelial cadherin expression and reduce vascular endothelial permeability, repairing the damage of vascular endothelial barrier caused by OSM.

[0017] As a preferred solution: the dosage form of the medicine includes capsules, oral liquids, granules, suspensions, solutions or injections; the administration route of the medicine is oral, intramuscular, subcutaneous or intravenous injection.

[0018] Compared with the prior art, the present application has obvious advantages and beneficial effects. Specifically, as known from the above technical solution, the compound provided by the present application exhibits significant beneficial effects in protecting lung vascular endothelial cells. The core advantage lies in its ability to efficiently inhibit OSM-induced endothelial barrier damage. By specifically targeting the pathological process induced by OSM, the compound can effectively reverse the down-regulation of the key adhesion junction protein VE-cadherin caused by OSM, enhance the integrity of the vascular endothelial barrier, significantly reduce the permeability of endothelial cells, and prevent the occurrence of plasma protein leakage and tissue edema. The compound can exert a clear protective effect at a low concentration range of 1-10 μM, showing a good dose-effect relationship and clinical application safety. It directly maintains the expression level of VE-cadherin protein, providing a precise treatment strategy for lung vascular barrier dysfunction-related diseases. The application of the compound in medicine has broad application prospects in the field of new drug development.

[0019] To make the structural features and effects of the present application clearer, specific embodiments will be described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 Figure 1 is a schematic diagram showing the effect of different concentrations of the compound of the present application on the viability of HULEC-5A cells for different times;

[0021] Figure 2 Figure 4 is a schematic diagram showing the effect of OSM and the compound of the present application on the expression of vascular endothelial cadherin;

[0022] Figure 3 Figure 5 is a schematic diagram showing the effect of OSM and the compound of the present application on endothelial permeability;

[0023] Figure 4 Figure 6 is a schematic diagram showing the effect of OSM and the compound of the present application on the transmembrane electrical impedance of endothelial cells;

[0024] Figure 5Schematic diagram of the compound of the present application protecting the vascular endothelial barrier damage caused by OSM in mice. DETAILED DESCRIPTION

[0025] The present application is as Figure 1 As shown in Figure 5, the materials, reagents, etc. used in the present application can be purchased commercially unless otherwise specified; a compound for use in the preparation of a drug for protecting lung vascular endothelial cells, the compound has a structural formula:

[0026] The compound is referred to as Formula I compound.

[0027] The chemical name of the Formula I compound used in the present application is: 3-[(2H-1, 3-benzodioxol-5-yl) methylene]-5-(4-methoxyphenyl) furan-2(3H)-one, containing a furanone core, a benzodioxolyl group and a 4-methoxyphenyl group.

[0028] Compound molecular formula: COc1ccc (cc1) C1=C\C (=C\c2ccc3OCOc3c2) C (=O) O1.

[0029] The compound is purchased from the United States TargetMol Company (No. 5639-0112) with a specification of 5.2 mg / bottle.

[0030] The drug includes the compound, which is the active ingredient of the drug; the compound is used as an inhibitor of OSM (oncostatin M) which causes barrier damage to endothelial cells. OSM as a vascular endothelial barrier damage cytokine, causes the expression of endothelial cell cadherin to decrease, the endothelial permeability to be damaged, leading to the destruction of the lung endothelial barrier function.

[0031] The compound is used as an active ingredient of the drug for inhibiting the damage of OSM to the endothelial cell barrier, and the dosage is 1-10 μM, and the treatment time of the compound to the endothelial cells is 12 hours.

[0032] The compound is used as an active ingredient of the drug for inhibiting the damage of OSM to the endothelial cell barrier, and the dosage is 10 μM.

[0033] The compound can be used as the only active ingredient of the drug, or compounded with other anti-vascular endothelial barrier damage active ingredients to form a compound drug, and play a role in protecting the lung vascular endothelial cells.

[0034] The drug also includes a solvent, an additive and a carrier, the solvent is DMSO, the additive is selected from polyethylene glycol 300, polysorbate 80, sulfobutyl-β-cyclodextrin or corn oil, and the carrier is selected from natural materials or semi-synthetic materials, the natural materials include gelatin, albumin, starch and chitosan; the semi-synthetic materials include hydrogenated soybean phospholipid and polyethylene glycol distearoyl phosphatidyl ethanolamine.

[0035] The composition of the solvent and the additive in the drug is: 10% DMSO plus 40% polyethylene glycol 300 plus 5% polysorbate 80 plus 45% physiological saline; or 10% DMSO plus 90% 20% sulfobutyl-β-cyclodextrin physiological saline solution, or 10% DMSO plus 90% corn oil.

[0036] The compound is used in the drug to inhibit the decrease of vascular epithelial cell VE-cadherin expression caused by OSM.

[0037] The compound is used in the drug to inhibit the increase of vascular endothelial cell permeability induced by OSM.

[0038] The compound is used in the drug to improve the decrease of vascular epithelial cell membrane electrical impedance caused by OSM, thereby protecting the cell barrier integrity.

[0039] The compound is used in the drug to up-regulate vascular endothelial cadherin expression and reduce vascular endothelial permeability, and repair the vascular endothelial barrier damaged by OSM.

[0040] The dosage form of the drug includes capsules, oral liquids, granules, suspensions, solutions or injections; the administration route of the drug is oral, intramuscular, subcutaneous or intravenous injection.

[0041] Example 1, detection of the toxicity of the compound of formula I to endothelial cells

[0042] Experimental method:

[0043] Cell culture: HULEC-5A cells were adherently cultured in MCDB131 medium containing 10% FBS, 10 ng / mL EGF, 1 μg / mL hydrocortisone, 10 mM L-glutamine and 1% streptomycin / penicillin antibiotics, and stably passaged and grown in a 5% CO2, 37°C constant temperature and humidity cell incubator.

[0044] Cell proliferation and toxicity detection: In order to detect whether the compound of formula I was toxic to HULEC-5A cells, the effect of different concentrations (1 μM, 5 μM, 10 μM and 25 μM) of the compound of formula I on the viability of HULEC-5A cells was detected by CCK8 reagent kit. The specific steps are as follows: (1) HULEC-5A cells were seeded in 96-well plates and cultured for 24 h. Then, the above different concentrations of the compound of formula I were added and cultured for another 12 h and 24 h. (2) After the drug treatment, 10 μL of CCK-8 reagent was added to each well. (3) After incubation in a 37℃ incubator for 1 h and 2 h respectively, the culture plates were taken out and the absorbance (OD value) at 450 nm was measured by microplate reader to calculate cell viability.

[0045] Experimental results:

[0046] like Figure 1 As shown, Figure 1 (A) represents the effect of compound I on the viability of HULEC-5A cells after 12 hours of treatment; Figure 1 (B) shows the effect of compound I treatment for 24 hours on the viability of HULEC-5A cells. **, ***, and **** represent P < 0.01, P < 0.001, and P < 0.0001, respectively, and ns represent P > 0.05. Figure 1 As shown in Figure (A), after 12 hours of treatment with compound I, the viability of HULEC-5A cells decreased with increasing compound concentration. Specifically, concentrations of compound I of 1-10 μM had no significant effect on HULEC-5A cell viability, indicating no significant cytotoxicity, while a concentration of compound I of 25 μM significantly reduced HULEC-5A cell viability. Figure 1 As shown in Figure (B), after 24 hours of treatment with the compound, the viability of HULEC-5A cells decreased with increasing concentration of the compound of Formula I. Considering the proliferative and toxic effects of this compound on HULEC-5A cells, this application concludes that after 12 hours of treatment with the compound of Formula I, at concentrations of 1-10 μM, it is safe and non-toxic to endothelial cells.

[0047] Example 2: Compound I improved the decrease in VE-cadherin expression in vascular epithelial cells caused by OSM.

[0048] Experimental methods:

[0049] Cell culture: HULEC-5A cells were adherent to MCDB131 containing 10% FBS, 10 ng / mL EGF, 1 μg / mL hydrocortisone, 10 mM glutamine and 1% streptomycin / penicillin antibiotics and were stably passaged in a 5% CO2, 37°C constant temperature and humidity cell culture incubator.

[0050] Cell immunofluorescence staining: HULEC-5A cells were seeded in 24-well plates at a density of 10 x 10 4 HULEC-5A cells were seeded in 24-well plates at a density of 10 x 10

[0051] Western blotting: 25 x 10 4 HULEC-5A cells were seeded in 6-well plates at a density of 25 x 10

[0052] Results: The compound of formula I improved the decrease in the expression of VE-cadherin in vascular epithelial cells caused by OSM

[0053] VE-cadherin is a core protein that controls the opening, closing and permeability changes of the endothelial barrier. As Figure 2Shown, Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm. Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm. Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm. Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm. Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm. Figure 2 Figure 7 shows the expression of VE-cadherin protein in HULEC-5a cells treated with 20 ng / mL OSM alone or in combination with compound I (10 uM) for 12 hours. The VE-cadherin protein was labeled with green fluorescence, and the cell nucleus was stained with DAPI to blue color. The scale bar = 20 pm.

[0054] In summary, the expression of VE-cadherin in vascular endothelial cells was reduced after treatment with human OSM recombinant protein for 12 hours. Compound I can inhibit the reduction of VE-cadherin expression induced by OSM.

[0055] Example 3, Inhibition of OSM-induced increased permeability of vascular endothelial cells by compound I

[0056] Experimental methods:

[0057] Cell culture: The culture method of HULEC-5a cells and the reagents used were the same as in Example 1.

[0058] In vitro cell permeability test 20 x 10^4 HULEC-5a cells per well were seeded evenly in the upper chamber of a 24-well transwell plate (3.0 um pore size), and divided into Ctrl group, OSM group and OSM + Formula I compound group, a total of 3 groups, each group of 3 replicates. After the cells were confluent into a monolayer, the OSM group was treated with 20 ng / mL OSM for 12 hours, and the OSM + Formula I compound group was treated with OSM and Formula I compound simultaneously for 12 hours. Subsequently, 100 uL of PBS containing FITC-dextran (1 ug / mL) was added to each upper chamber, and 500 uL of PBS without FITC-dextran (3000 MW) was added to the lower chamber. After incubation at 37°C for 10 minutes, the fluorescence intensity of FITC-dextran transferred to the lower chamber was measured using a multifunctional microplate reader, with excitation and emission wavelengths of 494 nm and 521 nm, respectively.

[0059] Experimental results: Formula I compound for inhibiting the increase in vascular endothelial cell permeability induced by OSM.

[0060] In vitro cell FITC-dextran permeability test can reflect the permeability of endothelium by the permeability of monolayer endothelial cells to FITC-dextran. The results of the cell permeability test (Figure 2) show that, Figure 3 Figure 3 The histogram shows the results of the relative permeability analysis of FITC-dextran in HULEC-5a cells treated differently. FITC: fluorescein isothiocyanate. Compared with the Ctrl group, the relative permeability of FITC-dextran in the OSM group increased (P = 0.005), and compared with the OSM group, the relative permeability of FITC-dextran in the OSM + Formula I compound group decreased (P = 0.036), indicating that Formula I compound improved the increase in endothelial cell permeability induced by OSM.

[0061] Example 4: Formula I compound improves the decrease in vascular epithelial cell membrane electrical impedance caused by OSM

[0062] Test method:

[0063] Cell culture: The method of culturing HULEC-5a cells and the reagents used were the same as in Example 1.

[0064] ​Cellular Trans-Epithelial Electrical Resistance Assay: 15 x 10^4 HULEC-5a cells were seeded in each well of the upper chamber of a 24-well transwell plate (3.0 um pore size). The cells were divided into Ctrl, OSM and OSM + Formula I compound groups, with 3 replicates in each group. After the cells adhered, the upper chamber was transferred to a trans-epithelial electrical resistance measurement instrument for incubation at 37°C in a constant humidity environment until the cells formed a monolayer. The OSM group was treated with 20 ng / mL OSM, and the OSM + Formula I compound group was treated with OSM and Formula I compound simultaneously. The trans-epithelial electrical resistance (TEER) value of each well of cells was detected in real time. After the TEER value was stable and no longer changed (the detection time was greater than 12 hours), the detection was stopped.

[0065] Experimental Results:

[0066] Endothelial Cell Trans-Epithelial Electrical Resistance Assay Results Figure 4 showed that Figure 4 The bar graph showed the trend of the trans-epithelial electrical resistance value of HULEC-5a cells treated differently over time (*: OSM group compared with Ctrl group, P<0.05; #: OSM group compared with OSM + Formula I compound, P<0.01, n=3); compared with the Ctrl group, the TEER value of the OSM group was significantly reduced (P<0.01), indicating that the cell barrier integrity was damaged; compared with the OSM group, the TEER value of the OSM + Formula I compound group was significantly increased (P<0.01), indicating that Formula I compound protected the cell barrier integrity.

[0067] Therefore, the above results all showed that OSM led to a decrease in the expression of intercellular adhesion proteins in vascular endothelial cells, an increase in endothelial permeability, and a destruction of the endothelial barrier; and Formula I compound played a protective role on the vascular endothelial barrier by inhibiting the action of OSM.

[0068] Example 5, Formula I Compound Reversed the Damage to Mouse Vascular Endothelial Barrier Caused by OSM

[0069] Experimental Materials:

[0070] Recombinant mouse OSM protein (495-MO-025, R&D Systems, USA), dextran fluorescein, 10000 MW (D1821, Invitrogen, USA). 6-8 week old C57BL / 6J male mice were purchased from Chongqing Tengxin Biotechnology Co., Ltd., and all animal experiments were conducted in accordance with the guidelines of the Southwest Jiaotong University Animal Protection and Utilization Committee.

[0071] Experimental Methods:

[0072] Animal modeling: C57BJ / 6J mice were randomly divided into three groups after adaptive feeding for 1 week: PBS treatment control group (PBS group), OSM treatment group (OSM group) and OSM + Formula I compound treatment group. After rapid anesthesia with 200ul isoflurane, the OSM group of mice inhaled OSM (500ng / each) into the lungs through the airway, and was treated for 24 hours; the OSM + Formula I compound treatment group was first injected with Formula I compound (10mg / kg) intraperitoneally, and then inhaled OSM (500ng / each) into the lungs through the airway, and was treated for 24 hours; the PBS group of mice was treated with the same volume of PBS. Finally, the mice were sacrificed by CO2 anesthesia, and the lung tissue was taken for frozen section.

[0073] Lung tissue immunofluorescence staining: The mouse lung tissue was soaked in 4% paraformaldehyde for 48 hours, then dehydrated in 30% sucrose solution for 48 hours, and then frozen for 24 hours after embedding with OCT. The frozen sections were cut with a thickness of 7 μm. Then, the tissue sections were permeabilized with 0.05% Tween20 for 10 minutes, incubated with 10% goat serum at room temperature for 1 hour to block non-specific antibodies, then incubated with VE-cadherin rabbit monoclonal antibody (1:400 dilution) at 4°C overnight, and goat anti-rabbit Alexa Fluor™ 488 antibody (1:1000 dilution) was combined with the primary antibody at room temperature for 2 hours. The cell nucleus was stained with DAPI, and then the section was observed by laser confocal microscope after mounting with anti-fluorescence quencher.

[0074] In vivo vascular permeability experiment: The dosage of each mouse was calculated according to 10mg / kg body weight of FITC-dextran. After anesthesia, the mice slowly inhaled 25μL of FITC-dextran (10000 MW) through each nostril, maintained a vertical body position for 2 min, until its breathing was stable. The mice were sacrificed after 1 h, the mice were disinfected with 70% ethanol, and the chest was opened with sterile forceps and surgical scissors to expose the heart apex. First, a slight negative pressure was applied to the plunger of a 1 mL syringe, and a 22 gauge needle was inserted into the heart apex. When blood appeared in the syringe, the plunger was gradually withdrawn to collect the blood. The collected blood was injected into an EP tube wetted with 10μL of EDTA (60mg / mL) in advance, and centrifuged at 550g for 10 minutes to collect the upper liquid. Then, the fluorescence OD value of plasma FITC-dextran was detected using a multifunctional microplate detector at an excitation wavelength of 485 nm and an emission wavelength of 528 nm.

[0075] Experimental results:

[0076] Recombinant mouse OSM protein was dropped into the mouse lung, and after 24 hours of treatment, the adhesion protein labeled by vascular endothelial VE-cadherin was detected by immunofluorescence to reflect the integrity of the endothelium. As shown in Figure 5 ,Figure 5 Figure 18C(A) is a confocal microscope observation of PBS group, OSM group and OSM + Formula I compound mouse lung tissue section VE-cadherin immunofluorescence staining, VE-cadherin is marked as green, DAPI stains the cell nucleus and is marked as blue, the scale = 20 μm. Figure 5 Figure 18C(B) is a bar chart showing the results of different treatment mouse vascular endothelial FITC-dextran permeability analysis (n = 4). The results are as follows Figure 5 Figure 18C(A) shows that compared with the PBS group, the OSM group of mice has reduced lung tissue VE-cadherin expression, and the endothelial integrity is damaged; compared with the OSM group, the OSM + Formula I compound group of mice has increased lung tissue VE-cadherin expression, and the endothelial integrity is restored. The FITC labeled FITC in the plasma is detected to reflect the change of vascular endothelial permeability, and the results are as follows Figure 5 Figure 18C(B) shows that compared with the PBS group, the OSM group of mice has increased FITC fluorescence in the plasma (P = 0.0004), indicating that the vascular endothelial permeability is increased; compared with the OSM group, the OSM + Formula I compound group of mice has reduced FITC fluorescence in the plasma (P = 0.023), indicating that the vascular endothelial permeability is reduced.

[0077] The design focus of the present application is that the compound provided by the present application exhibits significant beneficial effects in protecting lung vascular endothelial cells, and its core advantage is that it can efficiently inhibit OSM-induced endothelial barrier damage, and by specifically targeting the pathological process induced by OSM, the compound can effectively reverse the down-regulation of the key adhesion protein VE-cadherin caused by OSM, enhance the integrity of the vascular endothelial barrier, significantly reduce the permeability of endothelial cells, and prevent the occurrence of plasma protein leakage and tissue edema; the compound can exert a clear protective effect in a low concentration range of 1-10 μM, showing a good dose-effect relationship and clinical application safety; it directly maintains the expression level of VE-cadherin protein, providing a precise treatment strategy for lung vascular barrier dysfunction related diseases. The application of the compound in medicine has broad application prospects in the field of new drug development.

[0078] The above is only a preferred embodiment of the present application, and does not limit the technical scope of the present application in any way, so any slight modification, equivalent change and modification made according to the technical essence of the present application to the above embodiment are still within the scope of the technical solution of the present application.

Claims

1. The use of a compound in the preparation of a drug for protecting pulmonary vascular endothelial cells, characterized in that: The structural formula of the compound is: ； The medicine comprises the compound, the compound as an active ingredient of the medicine; the compound is used as an inhibitor of OSM causing barrier damage to endothelial cells.

2. Use according to claim 1, characterized in that: The compound is applied to the active ingredient of the medicine for inhibiting OSM damage to the endothelial cell barrier, the use dose is 1-10 μM, and the treatment time of the compound to the endothelial cells is 12 hours.

3. Use according to claim 2, characterized in that: The compound is applied to the active ingredient of the medicine for inhibiting OSM damage to the endothelial cell barrier, the use dose is 10 μM.

4. Use according to claim 1, characterized in that: The medicine further comprises a solvent, an additive and a carrier, the solvent is DMSO, the additive is selected from polyethylene glycol 300, polysorbate 80, sulfobutyl-beta-cyclodextrin or corn oil, and the carrier is selected from a natural material or a semi-synthetic material, the natural material comprises gelatin, albumin, starch and chitosan, and the semi-synthetic material comprises hydrogenated soybean phospholipid and polyethylene glycol distearoyl phosphatidyl ethanolamine.

5. Use according to claim 4, characterized in that: The composition of the solvent and the additive in the medicine is: 10% of DMSO plus 40% of polyethylene glycol 300 plus 5% of polysorbate 80 plus 45% of physiological saline; or 10% of DMSO plus 90% of a 20% sulfobutyl-beta-cyclodextrin physiological saline solution, or 10% of DMSO plus 90% of corn oil.

6. Use according to claim 1, characterized in that: The compound is used in the medicine for inhibiting the decrease of vascular epithelial cell VE-cadherin expression caused by OSM.

7. The use according to claim 1, characterized in that: The compound is used in the medicine for inhibiting the increase of vascular endothelial cell permeability induced by OSM.

8. The use according to claim 1, characterized in that: The compound is used in the medicine for improving the decrease of vascular epithelial cell membrane electrical impedance caused by OSM, thereby protecting the cell barrier integrity.

9. The use according to claim 1, characterized in that: The compound is used in the medicine for up-regulating vascular endothelial cadherin expression and reducing vascular endothelial permeability, and repairing the vascular endothelial barrier damaged by OSM.

10. The use according to claim 1, characterized in that: The dosage form of the medicine comprises a capsule, an oral liquid, a granule, a suspension, a solution or an injection; and the administration route of the medicine is oral, intramuscular, subcutaneous or intravenous injection.

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