Application of thiolutin in the prevention and / or treatment of radiation-induced lung injury

Abstract

The present invention relates to the fields of biology and medicine, and discloses the use of thiolutin in preventing and / or treating radiation-induced lung injury. Thiolutin prevents and / or treats radiation-induced lung injury induced by localized ionizing radiation exposure, including improving survival rates, inhibiting early acute radiation pneumonitis, improving long-term lung function, and inhibiting the development of pulmonary fibrosis. Therefore, it can be used as a potential drug for preventing and / or treating radiation-induced lung injury.

Description

Technical Field

[0001] The present invention relates to the fields of biology and medicine, and particularly to the use of thiolutin in preventing and / or treating radiation-induced lung injury. Background Art

[0002] Radiation-induced lung injury (RLI) is a disease caused by radiation exposure to the lungs, primarily encompassing early-stage acute radiation pneumonitis and long-term radiation-induced pulmonary fibrosis (RF). Acute RP manifests primarily as an inflammatory response in the alveoli, which in severe cases can rapidly lead to pulmonary edema, resulting in respiratory distress and decreased gas exchange. RF is a chronic, progressive disease characterized by the proliferation of fibrous tissue in the lungs, ultimately leading to lung failure. Currently, there is a lack of specific preventive and therapeutic medications for RLI, primarily relying on symptomatic supportive treatments such as oxygen delivery, analgesia, and anti-inflammatory therapy. Therefore, the development of drugs or methods to treat RLI is of great significance.

[0003] Thiolutin (THL) is a sulfur-based microbial antibiotic produced by Streptomyces with broad-spectrum antibacterial activity, but its research on radiation-induced lung injury has not been reported. Summary of the Invention

[0004] In order to overcome the above problems in the prior art, the present invention provides the use of thiolutein in preventing and / or treating radiation-induced lung injury.

[0005] A first aspect of the present invention provides the use of thiolutein in the preparation of a medicament for preventing and / or treating radiation-induced lung injury.

[0006] In the present invention, the radiation lung injury mainly refers to acute radiation lung injury, which refers to lung tissue damage caused by high-dose radiation exposure, usually occurring within a few weeks after high-dose radiation exposure. The main characteristics include inflammation and edema of the lung tissue, which causes symptoms such as dyspnea, cough, chest pain and fever. It is lung damage caused by local irradiation of ionizing radiation. The radiation lung injury is preferably lung damage caused by local irradiation of ionizing radiation. The radiation lung injury is a complication caused by radiotherapy of malignant tumors in the chest, that is, the object of prevention and / or treatment is patients with malignant tumors. Generally, malignant tumors that require radiotherapy are lung cancer, breast cancer, esophageal cancer or mediastinal malignant tumors. The ionizing radiation energy absorption dose of radiotherapy that is prone to produce radiation lung injury is 20-40Gy / time, and the number of times is 1-4.

[0007] The second aspect of the present invention provides the use of thiolutin in the preparation of a medicament for improving pulmonary interstitial congestion or alveolar structure (especially in patients with radiation-induced lung injury).

[0008] A third aspect of the present invention provides the use of thiolutin in the preparation of a medicament for ameliorating pulmonary edema, particularly pulmonary edema in patients with radiation-induced lung injury. Pulmonary edema is a pathological condition in which abnormal fluid infiltration from the pulmonary capillaries into the pulmonary interstitium and alveoli exceeds the compensatory capacity of lymphatic drainage, resulting in abnormal accumulation of fluid outside the pulmonary vessels.

[0009] Pulmonary macrophages, which differentiate from monocytes, are widely distributed within the pulmonary interstitium, with a high concentration around the ducts below the bronchioles and within the alveolar septa. The accumulation of pulmonary macrophages indicates lung inflammation. A fourth aspect of the present invention provides the use of thiolutin in the preparation of a medicament for reducing the number of pulmonary macrophages, particularly pulmonary macrophage accumulation or infiltration in patients with radiation-induced lung injury.

[0010] A fifth aspect of the present invention provides the use of thiolutin in the preparation of a medicament for improving lung function, particularly in patients with radiation-induced lung injury. "Lung function" primarily includes lung capacity, ventilation function, gas exchange function, and small airway function, specifically minute ventilation, instantaneous flow rate at 50% forced expiration, and maximum expiratory volume. Thiolutin can significantly improve these parameters.

[0011] The sixth aspect of the present invention provides the use of thiolutin in the preparation of a drug for inhibiting pulmonary fibrosis (especially pulmonary fibrosis in patients with radiation-induced lung injury). Pulmonary fibrosis refers to the end-stage lung changes of interstitial lung disease characterized by fibroblast proliferation, large amounts of extracellular matrix deposition, and destruction of lung tissue structure. By administering thiolutin, the lung tissue changes of patients with radiation-induced lung injury are milder, collagen fiber deposition and alveolar interstitial fibrous exudates are less, the area of ​​pulmonary fibrosis is reduced, and the expression levels of fibrosis-related marker proteins (such as matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9) and type I collagen α1) of the degree of pulmonary interstitial fibrosis are reduced.

[0012] The "prevention and / or treatment" in the present invention includes: relief of symptoms related to lung injury, including relief of inflammation and edema symptoms, and relief of symptoms such as dyspnea, cough, chest pain and fever.

[0013] In the present invention, there is no particular requirement for the administration method of thiolutin, but it is preferably at least one of intravenous injection, intramuscular injection, and subcutaneous injection. Those skilled in the art can formulate thiolutin into a specific dosage form, such as an injection, according to the administration method.

[0014] In the present invention, the patient may include mammals, such as mice or humans.

[0015] In the present invention, the dosage of thiolutin can be determined according to the patient's condition. Taking mice as an example, the dosage of thiolutin can be 50-150 mg / kg body weight / day.

[0016] Thioluteolin can prevent and / or treat radiation-induced lung injury in the local irradiation model of ionizing radiation, including improving survival rate, inhibiting early acute radiation pneumonitis (significantly improving symptoms such as "pulmonary interstitial congestion, pulmonary edema, mild thickening of the alveolar septum, damaged alveolar structure, obvious tissue exudation in the alveolar cavity, and increased inflammatory cell infiltration"), improving long-term lung function, and blocking the occurrence of pulmonary fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It shows that in Example 1 of the present invention, thiolutin improves the survival rate of mice after 25Gy and 30Gy chest irradiation;

[0018] Figure 2 It shows that in Example 2 of the present invention, thiolutin alleviates acute radiation pneumonia in mice induced by 25Gy chest irradiation;

[0019] Figure 3 The results show that, in Example 3 of the present invention, thiolutin improves the lung respiratory function of mice 18 weeks after 17.5 Gy chest irradiation;

[0020] Figure 4 It is shown that in Example 4 of the present invention, thiolutin inhibits pulmonary fibrosis in mice induced by 17.5 Gy chest irradiation. DETAILED DESCRIPTION

[0021] The present invention will be described in detail below through examples.

[0022] In the following examples, the number of mice in each treatment group was 10.

[0023] Example 1

[0024] This example is used to illustrate that thiolutin can improve the survival rate of mice under high-dose chest irradiation.

[0025] The mouse model of radiation-induced lung injury is a classic model for studying radiation-induced lung injury. Mouse chests are locally irradiated with a cobalt source at a dose rate of 200 cGy / min. Radiation causes DNA damage and the production of large amounts of reactive oxygen species in the mouse lungs. Within 1-2 weeks, the mice develop acute radiation-induced pneumonitis, and around 4-6 weeks, lung fibrosis develops. This progression is largely consistent with the human disease, making it a classic model for developing therapeutics for radiation-induced lung injury. Therefore, mice are used for this experiment.

[0026] 8-9 week old female C57BL / 6J mice, weighing 19-21 g, were irradiated with 25 Gy or 30 Gy of 60Co in the chest to establish a radiation lung injury model. The first intraperitoneal injection of THL was 6 hours after irradiation, and subsequent administration was once every 2 days at a dose of 1 mg / kg. After 25 Gy chest irradiation, mice in the control group died on days 6-10 after irradiation, and the survival rate within 30 days after irradiation was 41.7%. THL treatment increased the survival rate of mice to 75% after 30 days ( Figure 1 A). After 30 Gy chest irradiation, mice in the control group also died on days 6-10 after irradiation, and the survival rate within 30 days after irradiation was only 13.3%. THL treatment can increase the survival rate of mice to 46.73% ( Figure 1 B). As can be seen, THL can alleviate the severity of acute radiation-induced pneumonitis and improve mouse survival.

[0027] Example 2

[0028] This example is used to illustrate that thiolutin alleviates acute radiation pneumonia in mice induced by 25 Gy chest irradiation.

[0029] In the same manner as in Example 1, mice were irradiated with 25Gy of 60Co on their chests to establish a radiation lung injury model. Since mice began to die on the 6th day after irradiation, a systematic analysis of the lung tissue damage of mice one week after 25Gy chest irradiation was performed. The collected lung tissues were stained with HE (Solebo hematoxylin and eosin (HE) staining kit, G1120). The stained tissue sections were then observed under a microscope, and the Osman lung histology scoring standard was used to evaluate the pathological changes in the specimens, and the degree of lung inflammation was evaluated by a double-blind method. The HE staining results showed that one week after 25Gy irradiation, the lung interstitial congestion and edema of the mice in the control group were accompanied by mild thickening of the alveolar septum, damage to the alveolar structure, obvious tissue exudation in the alveolar cavity, and increased inflammatory cell infiltration; THL treatment can significantly improve the above damage, and the Osman score was significantly reduced ( Figure 2 AB).

[0030] In addition, the collected lung tissues were stained with F4 / 80+ to observe the changes in the number of macrophages in the tissues after acute radiation pneumonia. Ten fields of view were randomly selected from each F4 / 80+ stained section, and the number of inflammatory cells under the microscope was recorded using ImageJ software. The immunohistochemical results showed that the number of macrophages (F4 / 80+) in the lung tissues of mice in the THL group was significantly reduced ( Figure 2 CD).

[0031] Figure 2 In the table, “*” indicates p < 0.05, the same below. The above results show that THL treatment can significantly improve 25 Gy irradiation-induced acute radiation lung injury in mice.

[0032] Example 3

[0033] This example is used to illustrate that thiolutin can improve lung function after radiation.

[0034] 8-9 week old female C57BL / 6J mice, weighing 19-21 g, were irradiated with 17.5 Gy of 60Co in the chest to establish a radiation lung injury model. The first intraperitoneal injection of THL was 6 hours after irradiation, and subsequent administration was once every 2 days at a drug dosage of 1 mg / kg. At 18 weeks, by monitoring the changes in lung function parameters such as minute ventilation (MV), expiratory flow at 50% of forced expiration (EF50), and peak expiratory flow (PEF), the respiratory function status of mice after radiation can be evaluated and the progression of lung injury can be inferred. The EMKA awake small animal respiratory physiology detection system was used to detect various lung function parameters of mice 18 weeks after 17.5 Gy irradiation. The minute ventilation, expiratory flow at 50% of forced expiration, and peak expiratory volume of mice in the THL group were significantly higher than those in the control group ( Figure 3 ), indicating that THL can improve the lung function of mice after radiation.

[0035] Example 4

[0036] This example is used to illustrate that thiolutin can inhibit pulmonary fibrosis caused by chest irradiation.

[0037] Masson staining of the lung tissues of mice 24 weeks after 17.5 Gy irradiation in Example 3 showed that the control mice had significant collagen fiber deposition in the lung tissues, fibrous exudates in the alveolar spaces, and obvious fibrosis in the lung interstitium. Compared with the irradiation group, the lung tissues of the THL group had milder changes, with less collagen fiber deposition and fibrous exudates in the alveolar spaces, and a lower degree of pulmonary interstitial fibrosis ( Figure 4 A). Measurement of pulmonary fibrosis area showed that THL treatment significantly reduced the area of ​​pulmonary fibrosis after radiation ( Figure 4 B), the Ashcroft score of lung tissue in the THL group was also significantly lower than that in the control group ( Figure 4 C). Consistent with this, the expression of fibrosis-related marker proteins matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and type I collagen α1 (COL1A1) in the lung tissue of mice in the 24-week irradiation group was significantly upregulated, while THL treatment significantly reduced the expression levels of these three proteins ( Figure 4 D), Figure 4 In the table, "**" indicates p < 0.01. This indicates that THL treatment can inhibit 17.5 Gy radiation-induced lung fibrosis.

[0038] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. Use of thiolutin in the preparation of a medicament for preventing and / or treating radiation-induced lung injury.

2. The use according to claim 1, wherein The radiation-induced lung injury is lung injury caused by local irradiation with ionizing radiation.

3. The use according to claim 1, wherein: The radiation-induced lung injury is a complication caused by radiotherapy for malignant tumors in the chest.

4. The use according to claim 3, wherein: The malignant tumor is lung cancer, breast cancer, esophageal cancer or mediastinal malignant tumor.

5. The use according to claim 3 or 4, wherein: The ionizing radiation energy absorption dose of the radiotherapy is 20-40 Gy / time, and the number of radiotherapy times is 1-4.

6. Use of thiolutin in the preparation of drugs for improving pulmonary interstitial congestion or alveolar structure in radiation-induced lung injury.

7. Use of thiolutin in the preparation of a medicament for improving pulmonary edema in radiation-induced lung injury.

8. Use of thiolutin in the preparation of a drug for reducing the number of pulmonary macrophages in radiation-induced lung injury.

9. Use of thiolutin in the preparation of a drug for improving lung function in radiation-induced lung injury.

10. Use of thiolutin in the preparation of a drug for inhibiting pulmonary fibrosis in radiation-induced lung injury.

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