Application of 9-hydroxypentadecanoic acid in preparation of medicine for preventing and treating lung injury

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of 9-hydroxypentadecanoic acid in preparation of a medicine for preventing and treating lung injury. By constructing a radon inhalation-induced lung injury mouse model, after exposure at different radon levels, the weight of a mouse is reduced, the lung coefficient is increased, the tidal volume of the lung, the ventilation volume per minute and the maximum inspiration flow are reduced, the respiratory function is inhibited, the alveolar cavity of the mouse is abnormally expanded, the pulmonary septum is thickened and fractured, and more fibrin exudation is accompanied; the 9-hydroxypentadecanoic acid can be used for effectively inhibiting pulmonary fibrosis and lung injury due to obvious inflammatory infiltration beside bronchus, extravasated blood in small blood vessels and lung tissue collagen deposition, and 9-hydroxypentadecanoic acid is used for intragastric administration, so that the 9-hydroxypentadecanoic acid can be used for preventing and treating the lung injury, especially for preventing and treating the lung injury caused by radon exposure.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of 9-hydroxypentadecanoic acid in the preparation of medicines 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. In addition, due to the close connection between the lung and the outside world, it is the main place for pathogenic microorganisms to invade the environment. A variety of factors can trigger the occurrence of lung inflammation and cause lung damage.

[0003] Radon-222 ( 222 Radon (Rn) is a colorless and odorless environmental radioactive inert gas. It 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 by inhalation. After the radon in the air is inhaled by the human body, it produces high-linear alpha particle irradiation to the bronchial and lung epithelial cells, and diffuses from the lung epithelium through the blood, producing radiation effects on other tissues. Therefore, lung tissue is the main target organ of radon exposure. Long-term radon exposure can cause DNA and oxidative damage, inflammatory response, and lead to chronic lung diseases, including pulmonary fibrosis and lung cancer.

[0004] At present, radiation protection against radon exposure damage is mainly carried out at home and abroad by reducing radon concentration through physical methods to prevent radon hazards, such as site selection, building material selection, mechanical ventilation, improved mining methods and reduced radon precipitation during house construction. Radiation protection against radon exposure damage has always been a major problem, and there are few studies on related protective drugs or reagents for radon exposure damage. Summary of the invention

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

[0006] In order to achieve the above object, the present invention provides the use of 9-hydroxypentadecanoic acid in preparing products for preventing and treating lung injury.

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

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

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

[0010] Preferably, the lung injury comprises lung collagen deposition.

[0011] Preferably, the lung injury comprises an increase in lung index.

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

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

[0014] The present invention also provides a medicine for preventing and treating lung injury, wherein the effective ingredient of the medicine comprises 9-hydroxypentadecanoic acid.

[0015] Preferably, the drug is formulated as a single-use dosage form with 35 mg of 9-hydroxypentadecanoic acid per dose.

[0016] Beneficial effects:

[0017] The present invention finds that administration of 9-hydroxypentadecanoic acid can inhibit weight loss and increase of lung coefficient in mice, improve respiratory function, restore the decrease of lung tidal volume, minute ventilation and maximum inspiratory flow caused by lung injury, inhibit lung collagen deposition and fibrosis, prevent and treat lung injury, especially prevent and treat lung injury caused by radon exposure. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the embodiments are briefly introduced below.

[0019] Figure 1 This is a graph showing the changes in weight gain of mice after inhalation of different doses of radon in Example 1;

[0020] Figure 2 This is a graph showing the change in lung coefficient of mice after inhalation of different doses of radon in Example 1;

[0021] Figure 3 This is a graph showing the tidal volume test results of mice after inhalation of different doses of radon in Example 1;

[0022] Figure 4 This is a graph showing the minute ventilation test results of mice after inhalation of different doses of radon in Example 1;

[0023] Figure 5 This is a graph showing the maximum inspiratory flow rate test results of mice after inhalation of different doses of radon in Example 1;

[0024] Figure 6 The results of H&E staining of mouse lung tissue after inhalation of different doses of radon in Example 1; wherein the scale is 250 μm;

[0025] Figure 7 This is a diagram showing the H&E scoring results of mouse lung tissue after inhalation of different doses of radon in Example 1;

[0026] Figure 8The Masson staining results of mouse lung tissue after inhalation of different doses of radon in Example 1; wherein the scale is 250 μm;

[0027] Fig. 9 This is a diagram showing the results of the Masson quantitative analysis of mouse lung tissue after inhalation of different doses of radon in Example 1;

[0028] Fig.10 This is a graph showing the changes in weight gain of mice after inhalation of different doses of radon in Example 2;

[0029] Fig.11 This is a graph showing the change in lung coefficient of mice after inhalation of different doses of radon in Example 2;

[0030] Fig.12 This is a graph showing the tidal volume test results of mice after inhalation of different doses of radon in Example 2;

[0031] Fig.13 This is a graph showing the minute ventilation test results of mice after inhalation of different doses of radon in Example 2;

[0032] Fig.14 This is a graph showing the maximum inspiratory flow rate test results of mice after inhalation of different doses of radon in Example 2;

[0033] Fig.15 The results of H&E staining of mouse lung tissue after inhalation of different doses of radon in Example 2; wherein the scale is 250 μm;

[0034] Fig.16 This is a diagram showing the H&E scoring results of mouse lung tissue after inhalation of different doses of radon in Example 2;

[0035] Fig.17 The Masson staining results of mouse lung tissue after inhalation of different doses of radon in Example 2; wherein the scale is 250 μm;

[0036] Fig.18 This is a diagram showing the results of the Masson quantitative analysis of mouse lung tissue after inhalation of different doses of radon in Example 2;

[0037] In the figure, ns means no statistical significance, **** means p < 0.0001, *** means p < 0.001, ** means p < 0.01, and * means p < 0.05. DETAILED DESCRIPTION

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

[0039] As an embodiment, the product of the present invention is a medicine or a reagent; as an embodiment, the product of the present invention is a medicine.

[0040] As an embodiment, the lung injury described in the present invention includes lung injury caused by radon exposure. As an embodiment, the radon exposure described in the present invention has a relative cumulative exposure dose of 30 to 120 WLM; as another embodiment, the radon exposure described in the present invention has a relative cumulative exposure dose of 60 to 120 WLM. As an embodiment, the concentration of radon exposure described in the present invention is 100,000 Bq / m 3 , time is 189~755h; as another embodiment, the radon exposure concentration of the present invention is 100000 Bq / m 3 , the time is 377~755h.

[0041] The present invention constructs a mouse model of lung injury caused by radon inhalation and finds that after exposure to different radon levels, the mice lose weight, the lung coefficient increases, the lung tidal volume, minute ventilation and maximum inspiratory flow rate all decrease, the respiratory function is inhibited, the mouse alveolar cavity expands abnormally, the lung septum thickens and breaks, accompanied by more fibrin exudation, obvious inflammatory infiltration appears around the bronchus, congestion appears in small blood vessels, and collagen deposition in the lung tissue can lead to the occurrence of pulmonary fibrosis and lung injury. Oral administration of 9-hydroxypentadecanoic acid can effectively inhibit the above phenomena. Therefore, 9-hydroxypentadecanoic acid can be used for the prevention and treatment of lung injury, especially the prevention and treatment of lung injury caused by radon exposure.

[0042] The present invention also provides a medicine for preventing and treating lung injury, wherein the effective ingredient of the medicine comprises 9-hydroxypentadecanoic acid.

[0043] As an embodiment, the drug of the present invention is formulated as a single-use dosage form with 35 mg of 9-hydroxypentadecanoic acid per dose.

[0044] The present invention also provides a method for preventing and treating lung injury, which comprises intragastric administration of 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 drugs for preventing and treating lung injury is described in detail below in conjunction with the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

[0046] Example 1

[0047] 1. Experimental Materials

[0048] (1) Experimental animals: 18 C57 mice purchased from Spefoc Biotechnology.

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

[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 placed in an environment with a background radon concentration of 8.20 Bq / m 3 The mice in the radon exposure group were exposed to a HD-3 multifunctional radon chamber with a radon exposure concentration of 100,000 Bq / m 3 The exposure time of the control group and radon exposure group were 189, 377, and 755 h, respectively, and the relative cumulative exposure dose was 30, 60, and 120 working level months (WLM).

[0052] 3. Experimental testing and conclusions

[0053] (1) Pulmonary fibrosis may be accompanied by symptoms such as decreased appetite and weight loss. The lung coefficient is determined by dividing the wet weight of the lung (mg) by the body weight (g), and can dynamically reflect the progression of lung disease. With the development of lung inflammation and fibrosis, lung exudation increases, water increases, various proteins infiltrate the lung tissue, and the collagen content of the lung increases, leading to an increase in lung weight and a corresponding increase in the lung coefficient. Therefore, the dynamic changes in weight gain and lung coefficient of mice in different treatment groups after radon inhalation poisoning were detected; the weight gain was the body weight after exposure (g) minus the body weight before exposure (g); the lung coefficient was determined by dividing the wet weight of the lung (mg) by the body weight (g), and the test results are as follows: Figure 1 and Figure 2 As shown. Figure 1 and Figure 2 It can be seen that compared with the control group, the mice in the radon exposure group lost weight and increased lung coefficient after exposure to different radon levels. Radon exposure can cause pulmonary fibrosis and lung damage.

[0054] (2) The specific manifestations of pulmonary fibrosis are: 1. Decreased tidal volume (TV) and increased respiratory rate; 2. Decreased maximum inspiratory flow (PIF) and maximum expiratory flow; 3. Decreased mid-expiratory flow rate and minute ventilation (MV), etc. Therefore, the tidal volume (TV, mL), minute ventilation (MV, mL), maximum inspiratory flow rate (PIF, mL / s) and other parameters of the mice in the same treatment group after radon inhalation were detected by non-invasive small animal respirometer to reflect the lung function level of the mice. The results are as follows: Figures 3-5 As shown. Figures 3-5 It can be seen that exposure to different radon levels can reduce the tidal volume, minute ventilation and maximum inspiratory flow 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 subjected to H&E staining. Semi-quantitative lung pathology scoring 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 scores of three sections of each mouse were averaged, and the average of three mice in each group was again taken to finally obtain the lung injury score of the mice in that group. The results are shown in the figure. Figure 6 and Figure 7 As shown. Figure 6 and Figure 7 It can be seen that radon exposure caused abnormal expansion of the alveolar cavity of mice, thickening and rupture of the lung septum, accompanied by more fibrin exudation, obvious inflammatory infiltration around the bronchus, and congestion in small blood vessels. As the exposure dose accumulated, the degree of lung damage worsened.

[0056] (4) Masson staining was performed on lung tissue sections of mice in different treatment groups, and the collagen content was quantitatively analyzed using Image J software. The average value of three sections of each mouse was taken, and the average value of three mice in each group was taken again. Finally, the quantitative analysis results of collagen in the lung tissue of this group of mice were obtained. The results are shown in the figure. Figure 8 and Fig. 9 As shown. Figure 8 and Fig. 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 purchased from Spefco Biotechnology.

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

[0061] Vehicle solvent: composed of 10v / v% dimethyl sulfoxide (DMSO), 40v / v% polyethylene glycol (PEG300), 5v / v% Tween-80 and 45v / v% ddH2O;

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

[0063] Masson staining kit was purchased from Solebro.

[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 exposed to a HD-3 multifunctional radon chamber with a radon exposure concentration of 100,000 Bq / m 3 The exposure time was 377 and 755h, respectively, and the relative cumulative exposure dose was 60 and 120 working level months (WLM); among them, the mice in the metabolite intervention group were gavaged with 9-hydroxypentadecanoic acid (PEA) at a dosage of 35 mg / kg per day while being exposed to radon to construct a metabolite intervention mouse model; the mice in the solvent control group were gavaged with Vehicle solvent at a dosage of 35 mg / kg per day while being exposed to radon to construct a solvent control intervention mouse model.

[0066] 3. Experimental testing and conclusions

[0067] (1) The dynamic changes in weight gain and lung coefficient of mice in different treatment groups after radon inhalation were detected; the weight gain was the weight after exposure (g) minus the weight before exposure (g); the lung coefficient was obtained by dividing the lung wet weight (mg) by the body weight (g). The test results are as follows: Fig.10 and Fig.11 As shown. Fig.10 and Fig.11 It can be seen that 9-hydroxypentadecanoic acid can effectively inhibit the weight loss and increase of lung coefficient in radon-exposed mice, inhibit the occurrence of pulmonary fibrosis, and prevent and treat lung damage.

[0068] (2) Non-invasive small animal respirometer was used to detect the tidal volume (TV, mL), minute ventilation (MV, mL), maximum inspiratory flow rate (PIF, mL / s) and other parameters of the mice in the same treatment group after radon inhalation poisoning to reflect the lung function level of the mice. The results are as follows: Figures 12-14 As shown. Figures 12-14 It can be seen that 9-hydroxypentadecanoic acid can significantly improve the decrease in tidal volume, minute ventilation and maximum inspiratory flow of mice caused by radon exposure, improve lung function, and improve the lung function of mice after radon exposure.

[0069] (3) Lung tissue sections of mice in different treatment groups were subjected to H&E staining. Semi-quantitative lung pathology scoring 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 scores of three sections of each mouse were averaged, and the average of 5 to 6 mice in each group was again taken to finally obtain the lung injury score of the group of mice. The results are shown in the figure. Fig.15 and Fig.16 As shown. Fig.15 and Fig.16It can be seen that 9-hydroxypentadecanoic acid can significantly improve lung damage caused by radon exposure.

[0070] (4) Masson staining was performed on lung tissue sections of mice in different treatment groups, and the collagen content was quantitatively analyzed using Image J software. The average value of 3 sections for each mouse was taken, and the average value of 5 to 6 mice in each group was taken again. Finally, the quantitative analysis results of collagen in the lung tissue of this group of mice were obtained. The results are shown in the figure. Fig.17 and Fig.18 As shown. Fig.17 and Fig.18 It can be seen that 9-hydroxypentadecanoic acid can significantly improve collagen deposition and lung damage caused by radon exposure.

[0071] Based on the above content, it can be seen that 9-hydroxypentadecanoic acid can prevent and treat lung damage, especially lung damage caused by radon exposure.

[0072] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, 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.

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 any one of claims 1 to 6, characterized in that: The lung damage includes lung damage caused by radon exposure.

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

9. A drug for preventing and treating lung injury, characterized in that: The active ingredient of the drug includes 9-hydroxypentadecanoic acid.

10. The drug according to claim 9, characterized in that The drug is formulated as a single-use dosage form at 35 mg of 9-hydroxypentadecanoic acid / dose.

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