Application of dapanshuqing in preventing and / or treating acute radiation-induced lung injury

Abstract

The present invention relates to the fields of biology and medicine, and discloses the use of Dapansutrile (OLT1177) in the prevention and / or treatment of acute radiation-induced lung injury. The inventors of the present invention have found that Dapansutrile can prevent and / or treat acute radiation-induced lung injury in mice induced by local irradiation with ionizing radiation, including reducing the lung coefficient, alleviating pulmonary edema, inhibiting the aggregation of pulmonary macrophages, and reducing the secretion of serum inflammatory factors. Therefore, it can be used as a potential drug for the prevention and / or treatment of acute radiation-induced lung injury.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and particularly to the application of dapansutrile in the prevention and / or treatment of radiation-induced lung injury. Background Art

[0002] Acute radiation-induced lung injury refers to lung tissue damage caused by high-dose radiation exposure, usually occurring within 1-4 weeks after high-dose radiation exposure. The main characteristics include inflammation and edema of lung tissue, resulting in symptoms such as dyspnea, cough, chest pain, and fever. The occurrence of acute radiation pneumonitis not only limits the maximum dose of radiotherapy, reduces the effective control of the targeted tumor, but also causes symptoms such as decreased respiratory function, leading to a decline in the quality of life of radiotherapy patients. In severe cases, acute radiation pneumonitis may progress to respiratory failure and even threaten life. Currently, there is no effective treatment method clinically. Therefore, it is of great significance to study new strategies and drugs for the prevention and treatment of acute radiation-induced lung injury.

[0003] Dapansutrile (OLT1177) is a β-sulfonitrile compound, and it has been confirmed that it can treat gout attacks and experimental allergic asthma in mice. However, the role of OLT1177 in acute radiation-induced lung injury is still unclear. Summary of the Invention

[0004] In order to overcome the above problems existing in the prior art, the present invention provides the application of dapansutrile in the prevention and / or treatment of acute radiation-induced lung injury.

[0005] The first aspect of the present invention provides the application of dapansutrile in the preparation of a drug for the prevention and / or treatment of acute radiation-induced lung injury.

[0006] Dapansutrile is 3-methylsulfonylpropionitrile, and its structure is as follows:

[0007]

[0008] In the present invention, the acute radiation-induced lung injury refers to lung tissue damage caused by high-dose radiation exposure, usually occurring within several weeks after high-dose radiation exposure. The main characteristics include inflammation and edema of lung tissue, resulting in symptoms such as dyspnea, cough, chest pain, and fever, which is lung injury caused by local irradiation of ionizing radiation. The acute radiation-induced lung injury is preferably lung injury caused by local irradiation of ionizing radiation. The acute radiation-induced lung injury is a complication caused by radiotherapy for malignant tumors in the chest, that is, the object of prevention and / or treatment is patients with malignant tumors. Generally, the malignant tumors that require radiotherapy are lung cancer, breast cancer, esophageal cancer, or mediastinal malignant tumors. The absorbed dose of ionizing radiation energy for radiotherapy that is prone to cause acute radiation-induced lung injury is 20-40 Gy / time, and the number of times is 1-4.

[0009] The second aspect of the present invention provides the use of dapanshujing in the preparation of a drug for reducing the lung coefficient (especially the lung coefficient of patients with acute radiation-induced lung injury). The lung coefficient = lung wet weight (g) / body weight (kg) × 100%.

[0010] The third aspect of the present invention provides the use of dapanshujing in the preparation of a drug for alleviating pulmonary edema (especially the pulmonary edema of patients with acute radiation-induced lung injury).

[0011] Pulmonary macrophages are differentiated from monocytes and are widely distributed in the pulmonary interstitium, with a relatively large number around the ducts below the bronchioles and in the alveolar septa. The aggregation of pulmonary macrophages indicates the presence of inflammation in the lungs. The fourth aspect of the present invention provides the use of dapanshujing in the preparation of a drug for inhibiting the aggregation of pulmonary macrophages (or pulmonary macrophage infiltration, especially the aggregation or infiltration of pulmonary macrophages in patients with acute radiation-induced lung injury).

[0012] The fifth aspect of the present invention provides the use of dapanshujing in the preparation of a drug for reducing the secretion of serum inflammatory factors (especially the secretion of serum inflammatory factors in patients with acute radiation-induced lung injury).

[0013] In a preferred embodiment of the present invention, the inflammatory factors are selected from TNF-α and / or IL-6.

[0014] The "prevention and / or treatment" in the present invention includes: the remission of symptoms related to lung injury, including: the remission of inflammatory and edematous symptoms, and the remission of symptoms such as dyspnea, cough, chest pain, and fever.

[0015] In the present invention, there is no special requirement for the administration method of dapanshujing, but it is preferably at least one of intravenous injection, intramuscular injection, and subcutaneous injection. Those skilled in the art can formulate dapanshujing into a specific dosage form according to the administration method, such as an injection.

[0016] In the present invention, the patients may include mammals, such as mice or humans.

[0017] In the present invention, the dosage of dapanshujing can be determined according to the patient's condition. Taking mice as an example, the dosage of dapanshujing can be 50 - 150 mg / kg body weight / day.

[0018] Dapanshujing can reduce the lung coefficient, alleviate pulmonary edema, inhibit the aggregation of pulmonary macrophages, and reduce the secretion of serum inflammatory factors. Therefore, dapanshujing can be used as a potential drug for the treatment of acute radiation-induced lung injury. Description of the Drawings

[0019] Figure 1The figure shows the results of OLT1177 reducing the lung coefficient in acute radiation pneumonia;

[0020] Figure 2 The figure shows the results of OLT1177 alleviating lung tissue damage in acute radiation pneumonia;

[0021] Figure 3 The figure shows the results of OLT1177 inhibiting pulmonary macrophage infiltration in acute radiation pneumonia;

[0022] Figure 4 The figure shows the results of OLT1177 inhibiting the secretion of serum inflammatory factors in acute radiation pneumonia. Detailed implementation mode

[0023] The present invention will be described in detail below through examples. In the following examples, the number of mice in each treatment group is 10.

[0024] Example 1

[0025] Female C57BL / 6J mice aged about 8-10 weeks were irradiated with 60Co at the chest with 22 Gy to establish an acute radiation lung injury model. Specifically: 6 hours after cobalt source irradiation, the mice in the OLT1177 group and the IR+OLT1177 group were intraperitoneally injected with the OLT1177 solution at a dose of 100 mg / kg, and the control group (Ctrl) and the IR+NC group were injected with the same dose of solvent. Subsequently, they were intraperitoneally injected once a day at the same time, and the modeling time was 14 days. Then the mice were treated as follows:

[0026] (1) OLT1177 reduces the lung coefficient in acute radiation pneumonia

[0027] The lung coefficient is an important reference index for evaluating lung inflammation and edema. Therefore, when collecting the lung tissue of mice, the weight of the mice was first measured. Then the complete lungs of the mice were taken out, the connective tissue around the lungs was carefully removed, the blood stains on the surface of the lung tissue were rinsed with PBS buffer, and then the water on the surface of the lungs was carefully blotted dry with filter paper, placed on an electronic scale to weigh the weight of the lungs and recorded, and the lung coefficient value (%) = wet lung weight (g) / body weight (g) × 100% was calculated according to the formula. The results showed that the lung coefficient of the irradiated group of mice was significantly increased compared with that of the non-irradiated mice, but the lung coefficient of the IR+OLT1177 group was significantly decreased after irradiation, suggesting that OLT1177 may be able to reduce the inflammation level and edema of acute radiation pneumonia ( Figure 1 , "*" indicates p < 0.05, the same below).

[0028] (2) OLT1177 alleviates lung tissue damage in acute radiation pneumonia

[0029] To further explore the effects of dapanshuqing on alveolar structure and inflammatory exudation in acute radiation pneumonia, the collected lung tissues were stained with HE (Solarbio hematoxylin and eosin (HE) staining kit, G1120). Subsequently, the stained tissue sections were observed under a microscope. The pathological changes in the specimens were evaluated using the Osman histological scoring standard for lung tissues for the HE sections, and the degree of lung inflammation was evaluated by double-blind method. The results showed that there was no significant difference between the two groups of lung tissues in the control group and the group injected with dapanshuqing. The alveolar structures in both groups were clear, the alveolar septa were not widened, and there was no hemorrhage in the alveolar cavities. In the irradiation group, the alveolar septa were widened and accompanied by a large number of inflammatory cell infiltrations, pulmonary interstitial edema, and the alveolar structures were damaged to varying degrees. Compared with the irradiation control group, the inflammatory cell infiltration and inflammatory exudation in the lung tissues of the group injected with dapanshuqing after irradiation were reduced, the alveolar structures were relatively intact, and the degree of pulmonary interstitial edema was alleviated( Figure 2 ). The above results indicate that dapanshuqing alleviates lung tissue damage in acute radiation pneumonia.

[0030] (3) Dapanshuqing inhibits pulmonary macrophage infiltration in acute radiation pneumonia

[0031] At 14 days of radiation-induced lung injury, macrophages in the lung tissues increased significantly, and produced ROS and matrix metalloproteinases (MMP), promoting cell apoptosis. First, 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. Then, 10 fields of view were randomly selected from each section stained with F4 / 80+, and with the help of ImageJ software, the number of inflammatory cells under the microscope was recorded. There was no significant difference in the number of macrophages between the control group and the group injected with dapanshuqing. Compared with the control group, the number of macrophages in the lung tissues of the irradiated group of mice increased, while dapanshuqing treatment significantly reduced the number of macrophages in the lung tissues of mice( Figure 3 ). The above results indicate that dapanshuqing inhibits pulmonary macrophage infiltration in acute radiation pneumonia.

[0032] (4) Dapanshuqing inhibits the secretion of serum inflammatory factors in acute radiation pneumonia.

[0033] Acute radiation pneumonia can also cause an increase in the levels of serum cell inflammatory factors. Before collecting the lung tissues of mice, mouse serum samples were collected, and the effects of dapanshuqing on the secretion of inflammatory factors in the whole body serum of mice were detected using the cytometric bead array (CBA) technique for multi-index protein quantification of trace samples. The results showed that the levels of IL-6 and TNF-α in the serum of the irradiation group were significantly higher than those in the control group, and the levels of TNF-α and IL-6 in the serum of the group injected with dapanshuqing after irradiation decreased significantly( Figure 4 , "**" indicates p < 0.01; "****" indicates p < 0.0001).

[0034] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including the combination of each technical feature in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. Use of dapanoxacin in the preparation of a drug for preventing and / or treating acute radiation-induced lung injury.

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

3. The use according to claim 1, wherein: The acute radiation 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.

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