Application of Cryptoxanol in treatment of acute lung injury

Abstract

The invention provides an application of cryptoxanthin in treating acute lung injury, and belongs to the technical field of application of cryptoxanthin. The invention provides an application of Cryptoxanol in treatment of acute lung injury, the Cryptoxanol can be used independently or combined with other medicinal components for use, and can be prepared into tablets, capsules, electuary, drops, granules or injections for use. The Cryptotaxol can be applied to treatment of acute lung injury, a theoretical research basis is provided for application of Cryptotaxol to treatment of acute lung injury, and meanwhile, verification is further carried out by adopting mouse experiments, and theoretical and experimental basis is provided for clinical research.

Description

Technical Field

[0001] The invention relates to the technical field of application of cedarol, and in particular to application of cedarol in treating acute lung injury. Background Art

[0002] Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is an acute, progressive hypoxic respiratory failure caused by damage to the neutrophil-dependent and platelet-dependent pulmonary endothelium and epithelial barrier. ALI and ARDS have the same pathophysiological changes, and severe ALI or its final stage is defined as ARDS. Its main pathological basis is the damage to the pulmonary epithelial barrier and increased pulmonary microvascular permeability, which leads to the formation of pulmonary edema and hyaline membranes by protein-rich alveolar exudates, accompanied by pulmonary interstitial fibrosis, and even severe hypoxemia and impaired carbon dioxide excretion. The pathophysiological changes are mainly manifested as decreased lung compliance, increased intrapulmonary shunt, and ventilation / perfusion imbalance. The clinical manifestations are refractory hypoxemia, increased respiratory rate, and respiratory distress. Chest X-rays show diffuse infiltration shadows in both lungs, and multiple organ dysfunction may occur in the later stage.

[0003] Hinokitiol is a natural terpenoid compound found in the heartwood of the Cupressaceae plant (Chamaecyparis taiwanensis) and belongs to the lignan class of substances. It has a wide range of biological activities, including antibacterial, anti-inflammatory, antioxidant and anticancer properties. The chemical structure of hinokitiol is a monocyclic terpene, which shows significant lipid solubility, allowing it to easily penetrate the cell membrane and exert its effects. Various studies have shown that hinokitiol can exert anti-inflammatory and anti-cancer effects by regulating multiple signal transduction pathways, such as NF-κB, MAPK, PI3K / Akt / mTOR, etc.; in addition, it also exhibits anti-thrombotic potential by inhibiting platelet activation and promoting vascular smooth muscle cell proliferation; hinokitiol also has a certain mechanism of action in inhibiting pathogen infection, regulating cell cycle and inducing tumor cell apoptosis, making it a natural compound with multi-target therapeutic potential and good prospects for drug development.

[0004] Based on this, providing the application of cedarwood in the treatment of acute lung injury has important practical significance and can provide theoretical and experimental basis for new clinical research. Summary of the invention

[0005] The purpose of the present invention is to provide an application of cedarwood in treating acute lung injury, aiming to solve the technical problem that the therapeutic effect of cedarwood on acute lung injury has not been studied in the prior art.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides application of cryptomeria phenol in treating acute lung injury.

[0008] Furthermore, the cryptomeria phenol can be used alone or in combination with other medicinal ingredients.

[0009] Furthermore, the cryptomeria phenol can be made into tablets, capsules, granules, drops, granules or injections for use.

[0010] Furthermore, the use of cedarwood in treating acute lung injury includes using cedarwood for preparing a method for preventing and / or treating acute lung injury.

[0011] The present invention also provides a medicine for preventing and / or treating acute lung injury, comprising the effective ingredient cryptomeria phenol.

[0012] Compared with the prior art, the cryptomeria phenol described in the present invention can be used to treat acute lung injury, providing a theoretical research basis for the application of cryptomeria phenol in the treatment of acute lung injury, and further verified by mouse experiments, providing a theoretical and experimental basis for clinical research. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is a schematic diagram of the lung function test results of mice in the test example of the present invention;

[0014] Figure 2 This is a schematic diagram of acute lung injury in mice in the test example of the present invention;

[0015] Figure 3 Schematic diagram of the calculation results of Evans blue optical density values ​​(OD values) and right lung wet / dry weight ratio (Wet / Dry ratio) of the test example mice of the present invention;

[0016] Figure 4 Schematic diagram of superoxide dismutase activity (SOD activity) and malondialdehyde levels (MDA levels) in the lung tissue of mice in the test example of the present invention;

[0017] Figure 5 Schematic diagram of the pathological morphological examination results of mouse lung tissue in the test example of the present invention. DETAILED DESCRIPTION

[0018] The invention provides application of cryptomeria phenol in treating acute lung injury.

[0019] In the present invention, the cryptomeria phenol is used alone or in combination with other medicinal ingredients.

[0020] In the present invention, the cryptomeria phenol can be made into tablets, capsules, granules, drops, granules or injections for use.

[0021] In the present invention, the use of cedarwood in treating acute lung injury includes using cedarwood for preparing a method for preventing and / or treating acute lung injury.

[0022] The present invention also provides a medicine for preventing and / or treating acute lung injury, comprising the effective ingredient cryptomeria phenol.

[0023] In the present invention, unless otherwise specified, the required raw materials for preparation are all commercially available products well known to those skilled in the art.

[0024] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0025] Example 1

[0026] (1) Selection of experimental animals: 60 8-week-old C57BL / 6 mice were purchased from Vital River Experimental Animal Center and randomly divided into blank control group, model group, low-dose group (5 mg / kg), high-dose group (15 mg / kg) and positive drug (dexamethasone 5 mg / kg) control group according to body weight, with 12 mice in each group;

[0027] (2) Modeling: The five groups of mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (50 mg / kg), and then 5 mg / kg LPS was injected into the trachea using a microsyringe. After intratracheal instillation, the mice were kept vertical for 1 min to ensure the distribution of LPS or saline in the lungs;

[0028] (3) Drug administration: 6 hours after step (2), the mice were dosed according to the grouping set in step (1), once a day for 3 consecutive days;

[0029] (4) Testing: Twelve hours after administration on the third day, the mice were subjected to lung function tests and other experiments.

[0030] Test Case

[0031] The lung tissues of the mice described in Example 1 were taken, and the right lung wet / dry weight ratio (W / D), hematoxylin-eosin staining (H&E), and protein immunoblotting (Western blot) were used to observe and detect the pathological morphological changes of the lung tissues;

[0032] (1) Pulmonary function test was performed on the collected mouse lung tissue: the mice were anesthetized with 90 mg / kg sodium pentobarbital, the mouse trachea was exposed, and the spirometer (Chest, Tokyo, Japan) was connected at a frequency of 90. A computer monitoring scanner was used to record lung function-related parameters, including airway resistance (Raw), dynamic lung compliance (Cdyn), peak expiratory flow (PEF), and maximum expiratory midflow (MMF). The results are shown in Figure 2. Figure 1 shown; based on Figure 1 It can be seen that compared with the normal control group, the saline group showed the highest airway resistance (Raw Level) (2.41±2.89), and the dynamic lung compliance (Cdyn Level) (1.16±0.34) was significantly decreased. At the same time, the peak expiratory flow rate (PEF) (3.06±0.33) and the maximum mid-term flow rate (MMF) (2.04±0.12) were at the lowest level. These data indicate that the lung elasticity and expansion capacity of mice were impaired after ALI modeling, the airway obstruction was obvious, and the lung damage was the most serious; ALI mice given cedar phenol can significantly restore their lung function, making various indicators close to those of normal mice, and compared with the low-dose group, mice given high-dose cedar phenol significantly reduced (Raw Level). Level) (1.08±0.20), elevated Cdyn (2.16±0.31), (PEF) (5.26±0.58) and MMF (2.86±0.13) were similar to the positive drug dexamethasone group, and (RawLevel) (1.01±0.15), elevated Cdyn (2.08±0.33), (PEF) (5.47±0.58) and MMF (2.80±0.18) had lung function closer to normal levels.

[0033] (2) The Evans blue optical density values ​​(OD values) and the wet / dry weight ratio (Wet / Dry ratio) of the mice were calculated. The Evans blue optical density values ​​(OD values) were calculated as follows: EB (50 mg / kg) was injected into the femoral vein of each group of mice 15 minutes before being killed. The lungs were removed after thoracotomy and the surrounding tissues of the upper lobe of the right lung were removed. The lungs were immersed in formamide solution (1 mL / 100 mg animal body weight) and incubated at 45-50°C for 72 hours. After all the pigments in the tissues were leached out, the tissues were removed and centrifuged. The supernatant was taken and colorimetrically determined at 620 nm using a spectrophotometer. The optical density (OD) of the formamide solution was measured. The wet / dry weight ratio (Wet / Dry ratio) of the right lung was calculated as follows: The mice were killed 3 days after modeling, the right lung tissues were collected, the surface blood was removed, and the wet weight of the lungs was weighed; the lung tissues were dried at 60°C for 72 hours, the dry weight of the lungs was weighed, and the wet / dry weight ratio was calculated. The lung damage of the mice was judged. The results are as follows: Figure 2 and Figure 3 ;based on Figure 2 and Figure 3It can be seen that the normal saline group showed the highest Evans blue optical density value (OD values) and the highest right lung wet / dry weight ratio (Wet / Dry ratio), indicating that the lung tissue edema was the most serious and the microvascular damage was severe; the OD values ​​of the low-dose and high-dose groups of cedarwood were significantly lower than those of the normal saline group, and the high-dose group was close to the positive control group, both significantly lower than the normal saline group (P<0.01), close to the normal level, indicating that cedarwood may reduce microvascular permeability and help alleviate pulmonary edema.

[0034] (3) After grinding, pulverizing and centrifuging the lung tissue, the lung supernatant was extracted with physiological saline. According to the instructions, the superoxide dismutase activity (SOD activity) and malondialdehyde level (MDA levels) in the mouse lung tissue were detected using MDA (ab118970, Abcam, USA) and SOD (ab65354, Abcam, USA) detection kits to determine the oxidative stress level. The results are as follows: Figure 4 ;based on Figure 4 It can be seen that under normal circumstances, the level of oxidative stress in mice is low and the antioxidant system is in a stable state. The superoxide dismutase (SOD) activity of the normal saline group is the highest and the malondialdehyde (MDA) level is the lowest, indicating that the body attempts to resist oxidative stress through antioxidant mechanisms, but its high level is the result of oxidative stress response, and acute inflammatory stimulation leads to a sharp increase in free radicals in the lungs; the SOD activity of the low-dose and high-dose cedarwood groups is lower than that of the normal saline group, and the MDA level is higher than that of the normal saline group, indicating that oxidative stress is controlled and inflammation is reduced; the results suggest that cedarwood has the ability to stabilize the antioxidant system and is used to improve the inflammatory condition caused by acute lung injury.

[0035] (4) The collected mouse lung tissues were subjected to pathological morphological examination. Figure 5 ;based on Figure 5It can be seen that the lung tissue in the normal group was uniform in color, showing a healthy pink color, with a smooth surface and no obvious bleeding or congestion; its alveolar structure was clearly visible, the lung tissue structure was intact, the alveolar wall was thin, there was no obvious inflammatory cell infiltration and inflammatory substance exudation in the blood vessels and bronchi, there was no edema and congestion in the lungs, and the lung injury score was the lowest, indicating no signs of injury. H&E results showed that the alveolar structure of mice in the normal control group was clear and complete, the alveolar wall was uniform, the lung septum was thin, and the alveolar cavity was clean. The alveolar structure of mice in the saline group was unclear, the alveolar wall was uneven, the lung septum was thickened, and a large number of inflammatory cells exuded and accumulated in the alveolar cavity and septum. After low and high doses of cedarwood were given, the alveolar structure in the lung tissue sections of mice gradually became clear and complete, the degree of inflammatory cell infiltration gradually decreased, and the degree of interstitial edema or congestion gradually eased. The results of mice in the high-dose cedarwood group and the positive drug DEX 2mg / kg group were similar, with clearer and more complete alveolar structure, more uniform alveolar wall, slightly thickened lung septum, and reduced inflammatory cell exudation and infiltration. The degree of lung injury was evaluated and scored in a blinded manner based on four aspects: congestion and hemorrhage of the alveolar-capillary membrane, neutrophil infiltration or aggregation of air cavities or vascular walls, and thickness of alveolar wall / hyaline membrane formation. Each of the four components was scored from 0 to 4 points according to severity, and the final score ranged from 0 to 16 points as previously reported: the score of mice in the normal saline group was significantly higher than that of the control group, and both high-dose cedarwood and positive drugs could significantly reduce the lung injury score of mice.

[0036] Based on the above, it can be seen that cryptomeria phenol can exhibit significant anti-inflammatory protective effects in the mouse acute lung injury (ALI) model, and can effectively reduce lung inflammation and reduce the degree of edema.

[0037] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Application of cedarwood in the treatment of acute lung injury.

2. The use of cryptomeria phenol in the treatment of acute lung injury according to claim 1, characterized in that: The cryptomeria phenol can be used alone or in combination with other medicinal ingredients.

3. The use of cryptomeria phenol in the treatment of acute lung injury according to claim 1, characterized in that: The cryptomeria phenol can be prepared into tablets, capsules, granules, drops, granules or injections for use.

4. The use of cryptomeria phenol in the treatment of acute lung injury according to claim 1, characterized in that: The application of cedarwood in treating acute lung injury includes using cedarwood in preparing an application for preventing and / or treating acute lung injury.

5. A drug for preventing and / or treating acute lung injury, characterized in that: Contains the active ingredient cryptomeria.

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