Application of 9-hydroxypentadecanoic acid in the preparation of a drug for preventing and treating lung injury

Abstract

The present invention belongs to the technical field of biomedicine, and specifically relates to the application of 9-hydroxy pentadecanoic acid in the preparation of a drug for preventing and treating lung injury. By establishing a mouse model of radon inhalation-induced lung injury, the present invention found that after exposure to different radon levels, the body weight of the mice decreased, the lung coefficient increased, the tidal volume, minute ventilation volume and maximum inspiratory flow of the lungs decreased, the respiratory function was inhibited, the alveolar cavities of the mice were abnormally dilated, the lung septum was thickened and fractured, accompanied by more fibrin exudation, obvious inflammatory infiltration appeared beside the bronchi, congestion occurred in the small blood vessels, and collagen deposition occurred in the lung tissue, which could lead to the occurrence of pulmonary fibrosis and cause lung injury. By intragastric administration of 9-hydroxy pentadecanoic acid, the above phenomena can be effectively inhibited. Therefore, 9-hydroxy pentadecanoic acid can be used for the prevention and treatment of lung injury, especially for the prevention and treatment of lung injury caused by radon exposure.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to the application of 9-hydroxypentadecanoic acid in the preparation of drugs for preventing and treating lung injury. Background Art

[0002] As an important part of the respiratory system, the lung plays an important role in gas exchange and maintaining life activities. Moreover, due to the close connection between the lung and the outside world, it is the main place where pathogenic microorganisms in the environment invade. Multiple factors can trigger the occurrence of lung inflammation, resulting in the formation of lung injury.

[0003] Radon-222 ( 222 Rn) is a colorless and odorless environmental radioactive inert gas, which is the main source of natural radiation and has been announced by the World Health Organization as one of the main carcinogens. The main way for radon to enter the human body is inhalation. After the radon in the air is inhaled by the human body, it produces high-linear α-particle irradiation on bronchial and lung epithelial cells, and diffuses from the lung epithelium through the blood to produce radiation effects on other tissues. Therefore, the lung tissue is the main target organ of radon exposure. Long-term radon exposure can cause DNA and oxidative damage, inflammatory reactions, and lead to chronic lung diseases, including pulmonary fibrosis and lung cancer.

[0004] Currently, for the radiation protection of radon exposure damage, at home and abroad, it is mainly through physical methods to reduce the radon concentration to prevent radon hazards, such as site selection during house construction, selection of building materials, mechanical ventilation, improvement of mining methods, and reduction of radon exhalation. The radiation protection of radon exposure damage has always been a major problem, and there is little research on related protective drugs or reagents for radon exposure damage. Summary of the Invention

[0005] The purpose of the present invention is to develop related protective drugs or reagents for radon exposure damage and prevent and treat lung injury.

[0006] To achieve the above purpose, the present invention provides the application of 9-hydroxypentadecanoic acid in the preparation of products for preventing and treating lung injury.

[0007] Preferably, the lung injury includes lung respiratory function injury.

[0008] Preferably, the lung respiratory function injury includes one or more of decreased lung tidal volume, decreased minute ventilation volume, and decreased maximum inspiratory flow rate.

[0009] Preferably, the lung injury includes pulmonary fibrosis.

[0010] Preferably, the lung injury includes pulmonary collagen deposition.

[0011] Preferably, the lung injury includes an increase in lung coefficient.

[0012] Preferably, the lung injury includes lung injury caused by radon exposure.

[0013] Preferably, the relative cumulative exposure dose of radon for the radon exposure is 30 - 120 WLM.

[0014] The present invention also provides a drug for preventing and treating lung injury, and the active ingredient of the drug includes 9 - hydroxypentadecanoic acid.

[0015] Preferably, the drug is formulated in a dosage form for single use at a dose of 35 mg of 9 - hydroxypentadecanoic acid / dose.

[0016] Beneficial effects:

[0017] The present invention discovers that by administering 9 - hydroxypentadecanoic acid, it can inhibit the weight loss of mice and the increase in lung coefficient, improve respiratory function, restore the reduction in tidal volume, minute ventilation volume, and maximum inspiratory flow rate caused by lung injury, inhibit pulmonary collagen deposition and fibrosis, and prevent and treat lung injury, especially the prevention and treatment of lung injury caused by radon exposure. Description of the Drawings

[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the embodiments.

[0019] Figure 1 It is a graph showing the change results of the weight gain of mice after inhaling different doses of radon for example 1;

[0020] Figure 2 It is a graph showing the change results of the lung coefficient of mice after inhaling different doses of radon for example 1;

[0021] Figure 3 It is a graph showing the detection results of the tidal volume of mice after inhaling different doses of radon for example 1;

[0022] Figure 4 It is a graph showing the detection results of the minute ventilation volume of mice after inhaling different doses of radon for example 1;

[0023] Figure 5 It is a graph showing the detection results of the maximum inspiratory flow rate of mice after inhaling different doses of radon for example 1;

[0024] Figure 6 It is a graph showing the H&E staining results of the lung tissue of mice after inhaling different doses of radon for example 1; wherein, the scale bar is 250 μm;

[0025] Figure 7 It is a graph showing the H&E scoring results of the lung tissue of mice after inhaling different doses of radon for example 1;

[0026] Figure 8It is the Masson staining result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 1; wherein, the scale bar is 250μm;

[0027] Figure 9 It is the Masson quantitative analysis result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 1;

[0028] Figure 10 It is the result diagram of the change in the weight gain of mice after exposure to different doses of radon inhalation in Example 2;

[0029] Figure 11 It is the result diagram of the change in the lung coefficient of mice after exposure to different doses of radon inhalation in Example 2;

[0030] Figure 12 It is the result diagram of the tidal volume detection of mice after exposure to different doses of radon inhalation in Example 2;

[0031] Figure 13 It is the result diagram of the minute ventilation volume detection of mice after exposure to different doses of radon inhalation in Example 2;

[0032] Figure 14 It is the result diagram of the maximum inspiratory flow rate detection of mice after exposure to different doses of radon inhalation in Example 2;

[0033] Figure 15 It is the H&E staining result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 2; wherein, the scale bar is 250μm;

[0034] Figure 16 It is the H&E scoring result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 2;

[0035] Figure 17 It is the Masson staining result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 2; wherein, the scale bar is 250μm;

[0036] Figure 18 It is the Masson quantitative analysis result diagram of mouse lung tissue after exposure to different doses of radon inhalation in Example 2;

[0037] Among them, ns in the figure indicates no statistical significance, **** indicates p<0.0001, *** indicates p<0.001, ** indicates p<0.01, and * indicates p<0.05. Detailed implementation mode

[0038] The present invention provides the application of 9-hydroxypentadecanoic acid in the preparation of products for preventing and treating lung injury.

[0039] As an implementation mode, the product of the present invention is a drug or a reagent; as an implementation mode, the product of the present invention is a drug.

[0040] As an implementation manner, the lung injury described in the present invention includes lung injury caused by radon exposure. As an implementation manner, the relative cumulative exposure dose of radon in the radon exposure described in the present invention is 30 - 120 WLM; as another implementation manner, the relative cumulative exposure dose of radon in the radon exposure described in the present invention is 60 - 120 WLM. As an implementation manner, the concentration of the radon exposure described in the present invention is 100,000 Bq / m 3 ³, and the time is 189 - 755 h; as another implementation manner, the concentration of the radon exposure described in the present invention is 100,000 Bq / m 3 ³, and the time is 377 - 755 h.

[0041] By constructing a mouse model of lung injury caused by radon inhalation, the present invention finds that after exposure to different radon levels, the body weight of mice decreases, the lung coefficient increases, the tidal volume, minute ventilation volume, and maximum inspiratory flow of the lungs all decrease, the respiratory function is inhibited, the alveolar cavities of the mice are abnormally dilated, the lung septum is thickened and fractured, accompanied by more fibrin exudation, obvious inflammatory infiltration appears beside the bronchi, congestion appears in the small blood vessels, and collagen deposition occurs in the lung tissue, which can lead to the occurrence of pulmonary fibrosis and cause lung injury. Intragastric administration of 9 - hydroxypentadecanoic acid can effectively inhibit the above - mentioned phenomena. Therefore, 9 - hydroxypentadecanoic acid can be used for the prevention and treatment of lung injury, especially for the prevention and treatment of lung injury caused by radon exposure.

[0042] The present invention also provides a drug for preventing and treating lung injury, and the active ingredient of the drug includes 9 - hydroxypentadecanoic acid.

[0043] As an implementation manner, the drug described in the present invention is formulated into a single - use dosage form at a dose of 35 mg of 9 - hydroxypentadecanoic acid / dose.

[0044] The present invention also provides a method for preventing and treating lung injury, which is to intragastrically administer the drug described in the above technical solution.

[0045] To further illustrate the present invention, the application of 9 - hydroxypentadecanoic acid provided by the present invention in the preparation of a drug for preventing and treating lung injury will be described in detail below in conjunction with the drawings and examples, but they should not be construed as limiting the protection scope of the present invention.

[0046] Example 1

[0047] 1. Experimental materials

[0048] (1) Experimental animals: 18 C57 mice, purchased from SpfBioscience.

[0049] (2) Experimental reagents: H&E staining kit, purchased from Solarbio; Masson staining kit, purchased from Solarbio.

[0050] 2. Model construction

[0051] The experimental mice were randomly divided into a control group (NC) and a radon exposure group (Rn), with 9 mice in each group. The mice in the control group were raised under the condition of a background radon concentration of 8.20 Bq / m 3 ; the mice in the radon exposure group were respectively exposed as a whole to an HD-3 type multi-functional radon chamber, and the radon exposure concentration was 100000 Bq / m 3 ; the exposure times of the control group and the radon exposure group were 189, 377, and 755 h respectively, and the relative cumulative exposure doses were 30, 60, and 120 working level months (WLM).

[0052] 3. Experimental detection and conclusions

[0053] (1) Pulmonary fibrosis may be accompanied by symptoms such as decreased appetite and weight loss. The lung coefficient is measured by dividing the wet lung weight (mg) by the body weight (g), and can dynamically reflect the progression of lung diseases. With the development of pulmonary inflammation and fibrosis, there is an increase in lung exudation, an increase in water content, infiltration of various proteins into the lung tissue, and an increase in the collagen content of the lung, resulting in an increase in lung weight and a corresponding increase in the lung coefficient. Therefore, the dynamic changes in the weight gain of mice in different treatment groups after radon inhalation exposure and the changes in the lung coefficient were detected; among them, the weight gain was the body weight (g) after exposure minus the body weight (g) before exposure; the lung coefficient was obtained by dividing the wet lung weight (mg) by the body weight (g), and the detection results are as Figure 1 and Figure 2 shown. According to Figure 1 and Figure 2 , it can be seen that compared with the control group, the mice in the radon exposure group showed weight loss and an increase in the lung coefficient after exposure to different radon levels. Radon exposure can cause the occurrence of pulmonary fibrosis and lung injury.

[0054] (2) Since the specific manifestations of pulmonary fibrosis are: 1. Decrease in tidal volume (TV) and increase in respiratory rate; 2. Decrease in peak inspiratory flow (PIF) and peak expiratory flow; 3. Decrease in mid-expiratory flow rate and minute ventilation volume (MV), etc. Therefore, a non-invasive small animal respirator was used to detect parameters such as tidal volume (TV, mL), minute ventilation volume (MV, mL), and peak inspiratory flow rate (PIF, mL / s) of mice in the same treatment group after radon inhalation exposure to reflect the lung function level of the mice. The results are as Figures 3 - 5 shown. According to Figures 3 - 5 , it can be seen that exposure to different radon levels can reduce the tidal volume, minute ventilation volume, and peak inspiratory flow rate of mice, indicating that the lung respiratory function of mice is inhibited, which is common in restrictive lung diseases such as pulmonary fibrosis.

[0055] (3)Lung tissue sections of mice in different treatment groups were taken for H&E staining, and semi-quantitative pathological scoring of the lungs was performed according to the method of Szapiel et al. (doi: 10.1164 / arrd.1979.120.4.89; doi: 10.1136 / jcp.41.4.467) to quantify the degree of lung injury. The average value of the scores of 3 sections per mouse was taken, and then the average value of 3 mice per group was taken. Finally, the lung injury score of the mice in this group was obtained. The results are as Figure 6 and Figure 7 shown. According to Figure 6 and Figure 7 , it can be seen that radon exposure caused abnormal dilation of the alveolar lumen in mice, thickening and rupture of the interalveolar septum, accompanied by more fibrin exudation, obvious inflammatory infiltration beside the bronchi, and congestion in small blood vessels. With the accumulation of the exposure dose, the degree of lung injury increased.

[0056] (4)Lung tissue sections of mice in different treatment groups were taken for Masson staining, and Image J software was used for quantitative analysis of collagen content. The average value of 3 sections per mouse was taken, and then the average value of 3 mice per group was taken. Finally, the quantitative analysis results of collagen in the lung tissue of the mice in this group were obtained. The results are as Figure 8 and Figure 9 shown. According to Figure 8 and Figure 9 , it can be seen that exposure to different radon levels promoted collagen deposition in the lung tissue of mice to varying degrees.

[0057] Example 2

[0058] 1. Experimental materials

[0059] (1)Experimental animals: 24 C57 mice were purchased from SpfBioscience.

[0060] (2)Experimental reagents: 9-hydroxypentadecanoic acid (PEA), CAS number: 38076-46-9;

[0061] Vehicle solvent: composed of 10 v / v% dimethyl sulfoxide (DMSO), 40 v / v% polyethylene glycol (PEG300), 5 v / v% Tween-80, and 45 v / v% ddH 2 O;

[0062] H&E staining kit, purchased from Solarbio;

[0063] Masson staining kit, purchased from Solarbio.

[0064] 2. Model construction

[0065] The experimental mice were randomly divided into a solvent control group (Rn+Vehicle) and a metabolite intervention group (Rn+PEA), with 12 mice in each group. They were respectively exposed to an HD-3 type multi-functional radon chamber, and the radon exposure concentration was 100,000 Bq / m 3 , and the exposure times were 377 h and 755 h respectively, and the relative cumulative exposure doses were 60 and 120 working level months (WLM). Among them, the mice in the metabolite intervention group were intragastrically administered 9-hydroxy pentadecanoic acid (PEA) at a dose of 35 mg / kg every day during radon exposure to construct a metabolite intervention mouse model; the mice in the solvent control group were intragastrically administered Vehicle solvent at a dose of 35 mg / kg every day during radon exposure to construct a solvent control intervention mouse model.

[0066] 3. Experimental detection and conclusions

[0067] (1) Detect the dynamic changes in the weight gain and the changes in the lung coefficient of mice in different treatment groups after radon inhalation exposure. Among them, the weight gain is the weight after exposure (g) minus the weight before exposure (g); the lung coefficient is obtained by dividing the wet lung weight (mg) by the body weight (g). The detection results are as Figure 10 and Figure 11 shown. According to Figure 10 and Figure 11 , it can be seen that 9-hydroxy pentadecanoic acid can effectively inhibit the weight loss and the increase in the lung coefficient of radon-exposed mice, inhibit the occurrence of pulmonary fibrosis, and prevent and treat lung injury.

[0068] (2) Detect parameters such as tidal volume (TV, mL), minute ventilation volume (MV, mL), and peak inspiratory flow (PIF, mL / s) of mice in different treatment groups after radon inhalation exposure through a non-invasive small animal respirator to reflect the lung function level of the mice. The results are as Figures 12 - 14 shown. According to Figures 12 - 14 , it can be seen that 9-hydroxy pentadecanoic acid can significantly improve the reduction in tidal volume, minute ventilation volume, and peak inspiratory flow caused by radon exposure in mice, improve lung function, and improve the lung function of mice after radon exposure.

[0069] (3) Take lung tissue sections of mice in different treatment groups for H&E staining, and perform semi-quantitative pathological scoring of the lungs according to the method of Szapiel et al. (doi: 10.1164 / arrd.1979.120.4.89; doi: 10.1136 / jcp.41.4.467) to quantify the degree of lung injury. The average value of the scores of 3 sections of each mouse is taken, and then the average value of 5-6 mice in each group is taken to finally obtain the lung injury score of the mice in this group. The results are as Figure 15 and Figure 16 shown. According to Figure 15 and Figure 16It can be seen that 9-hydroxy pentadecanoic acid can significantly improve lung injury caused by radon exposure.

[0070] (4) Take lung tissue sections of mice in different treatment groups for Masson staining, and use Image J software for quantitative analysis of collagen content. Take the average value of 3 sections per mouse, and then take the average value of 5-6 mice in each group. Finally, obtain the quantitative analysis results of lung tissue collagen in this group of mice. The results are as Figure 17 and Figure 18 shown. According to Figure 17 and Figure 18 It can be seen that 9-hydroxy pentadecanoic acid can significantly improve collagen deposition caused by radon exposure and improve lung injury.

[0071] From the above content, it can be seen that 9-hydroxy pentadecanoic acid can prevent and treat lung injury, especially the prevention and treatment of lung injury caused by radon exposure.

[0072] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on this embodiment without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

Application of 1.9-hydroxypentadecanoic acid in the preparation of products for preventing and treating lung injury; the lung injury is lung injury caused by radon exposure.

2. The use according to claim 1, characterized in that: The lung injury includes lung respiratory function injury.

3. The use according to claim 2, characterized in that: The pulmonary respiratory function impairment includes one or more of decreased pulmonary tidal volume, decreased minute ventilation, and decreased maximum inspiratory flow.

4. The use according to claim 1, characterized in that: The lung damage includes pulmonary fibrosis.

5. The use according to claim 1, characterized in that: The lung damage includes lung collagen deposition.

6. The use according to claim 1, characterized in that: The lung damage includes an increase in lung volume.

7. The use according to claim 1, characterized in that: The relative cumulative exposure dose of radon in the radon exposure is 30~120WLM.

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