Use of substance with prussian blue structure in prevention and treatment of pulmonary fibrosis diseases

Abstract

The present invention provides use of a substance with a Prussian blue structure in the prevention and treatment of pulmonary fibrosis. The Prussian blue structure is a face-centered cubic unit cell comprising X ions, M ions, and cyanide ions. A space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to nitrogen atoms of cyanide, the M ions are connected by carbon atoms of cyanide, the carbon atoms are alternately coordinated to form a cubic unit cell, and the open framework structure of the Prussian blue has some gap sites and vacancies where A cations can be inserted.

Description

Application of substances with Prussian blue structure in the prevention and treatment of pulmonary fibrosis Technical Field

[0001] The invention belongs to the field of biotechnology, and particularly relates to the application of a substance with a Prussian blue structure in the treatment of diseases. Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, and fatal interstitial pneumonia with unknown etiology. It is predominantly affecting the elderly, with lesions confined to the lungs. It has been dubbed "a cancer that is not cancer" and is one of the most dangerous interstitial lung diseases, with a five-year survival rate of less than 30%. Its histological and / or imaging features resemble those of conventional interstitial pneumonia, primarily manifested by diffuse alveolitis, disorganized alveolar unit structure, and the formation of pulmonary fibrosis. Pulmonary function tests reveal decreased lung compliance, reduced lung capacity, reduced diffusion capacity, and an imbalance in ventilation / perfusion ratio, ultimately leading to respiratory failure and death.

[0003] IPF is the most common clinical form of idiopathic interstitial pneumonia, with a significant increase in prevalence in recent years. An epidemiological study of IPF showed a prevalence of 14-42.7 cases per 100,000 population in the United States, with an annual incidence of 6.8-16.3 cases per 100,000 population. While epidemiological data are lacking in my country, clinical practice has shown an increasing trend in IPF cases in recent years. Currently, there is no effective treatment other than lung transplantation, and the median survival of patients after diagnosis is only 2.5-3.5 years. However, the natural course and outcome of IPF vary greatly. Most patients experience a slow, gradual, and predictable decline in lung function; a minority experience recurrent exacerbations; and a very small minority experience rapid, progressive disease progression, with a 5-year survival rate of less than 40%, representing an extremely poor prognosis. Currently, clinical treatment options for IPF are very limited, with only two targeted therapies available: pirfenidone and nintedanib. While both can slow the decline in vital capacity, their efficacy is limited and they are associated with significant side effects. Developing effective drugs to treat IPF to meet clinical needs and save patients' lives is extremely urgent and has important clinical significance.

[0004] The pathogenesis of IPF remains unclear. It is generally believed that IPF originates from damage to the alveolar epithelium and abnormal repair after injury, and that alveolitis may be an early event in the disease. Treatment options for IPF mainly include glucocorticoids, immunosuppressants, and anti-fibrotic drugs (such as pirfenidone and nintedanib), but these methods have not been significantly effective in clinical trials and have varying degrees of toxic side effects. As the disease progresses, the only treatment option is lung transplantation.

[0005] While studying substances having a Prussian blue structure, the present inventors discovered that substances having this type of structure have a significant inhibitory effect on the occurrence and development of pulmonary fibrosis, and accordingly completed the present invention. Summary of the Invention

[0006] In a first aspect, the present invention provides a pharmaceutical composition for preventing and / or treating pulmonary fibrosis, the pharmaceutical composition comprising a substance having a Prussian blue structure, wherein the Prussian blue structure is a face-centered cubic unit cell composed of X ions, M ions, and cyanide ions, and the space group is generally referred to as Fm3m; in the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, the M ions are connected to the carbon atoms of the cyanide, and the carbon atoms are alternately coordinated to form a cubic unit cell, and cations A are inserted into the interstitial sites and vacancies of the open framework structure of the Prussian blue;

[0007] wherein A is selected from one or more of NH4, Li, Na and K cations, preferably K and / or Na;

[0008] X is selected from one or more combinations of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag and Gd metal ions, preferably Fe, Mn and / or Zn;

[0009] M is selected from one or more transition metal ions having a variable valence among Mn, Fe and Co, preferably Fe and / or Co.

[0010] Furthermore, the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.

[0011] Furthermore, the composition also contains other active ingredients for treating pulmonary fibrosis diseases, and the active ingredients for treating pulmonary fibrosis diseases are selected from glucocorticoids, immunosuppressants, pirfenidone and / or nintedanib.

[0012] In a second aspect, the present invention provides a use of a substance having a Prussian blue structure in the preparation of a medicament for preventing and / or treating pulmonary fibrosis. The Prussian blue structure is a face-centered cubic unit cell composed of X ions, M ions, and cyanide ions, and the space group is generally referred to as Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, and the M ions are connected to the carbon atoms of the cyanide. The carbon atoms are alternately coordinated to form a cubic unit cell, and cations A are inserted into the interstitial sites and vacancies of the open framework structure of the Prussian blue.

[0013] wherein A is selected from one or more of NH4, Li, Na and K cations, preferably K and / or Na;

[0014] X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag and Gd, preferably Fe, Mn and / or Zn;

[0015] M is selected from one or more transition metal ions having a variable valence among Mn, Fe and Co, preferably Fe and / or Co.

[0016] Furthermore, the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.

[0017] The substance with the Prussian blue structure as an active ingredient effectively improves pulmonary fibrosis by reducing collagen fiber deposition in lung tissue, reducing inflammatory cell infiltration, and improving disordered alveolar structure.

[0018] In a third aspect, the present invention provides a pharmaceutical composition comprising a substance having a Prussian blue structure and bleomycin, wherein the substance having a Prussian blue structure can alleviate the side effects of pulmonary fibrosis caused by bleomycin.

[0019] The Prussian blue structure is a face-centered cubic unit cell, composed of X ions, M ions and cyanide ions, and the space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, and the M ions are connected to the carbon atoms of the cyanide. The carbon atoms are alternately coordinated to form a cubic unit cell, and the cation A is inserted into the interstitial sites and vacancies of the open framework structure of Prussian blue.

[0020] wherein A is selected from one or more of NH4, Li, Na and K cations, preferably K and / or Na;

[0021] X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag and Gd, preferably Fe, Mn and / or Zn;

[0022] M is selected from one or more transition metal ions having a variable valence among Mn, Fe and Co, preferably Fe and / or Co.

[0023] Furthermore, the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.

[0024] In a fourth aspect, the present invention provides a use of a substance having a Prussian blue structure in preparing a preparation for reducing the side effects of bleomycin, wherein the side effects of bleomycin refer to the effects of pulmonary fibrosis caused by bleomycin.

[0025] The Prussian blue structure is a face-centered cubic unit cell, composed of X ions, M ions and cyanide ions, and the space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, and the M ions are connected to the carbon atoms of the cyanide. The carbon atoms are alternately coordinated to form a cubic unit cell, and the cation A is inserted into the interstitial sites and vacancies of the open framework structure of Prussian blue.

[0026] wherein A is selected from one or more of NH4, Li, Na and K cations, preferably K and / or Na;

[0027] X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag and Gd, preferably Fe, Mn and / or Zn;

[0028] M is selected from one or more transition metal ions having a variable valence among Mn, Fe and Co, preferably Fe and / or Co.

[0029] Furthermore, the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Representative CT images of the lungs of mice in each group;

[0031] Figure 2 Macroscopic images of lung tissues of mice in each group (the area within the yellow dotted line indicates the fibrosis lesion site);

[0032] Figure 3 H&E staining of lung tissues of mice in each group (the second column is the enlarged image in the red circle of the first column);

[0033] Figure 4 Masson staining of lung tissues of mice in each group (the second column is the enlarged image in the black circle of the first column);

[0034] Figure 5: Subpopulation breakdown of mononuclear phagocytes in lung tissues of mice in each group;

[0035] Figure 6: Subdivision of macrophage subsets and their functional scores in the lung tissues of mice in each group;

[0036] Figure 7: Interaction between Fabp5 subset macrophages and alveolar macrophages in lung tissues of mice in each group;

[0037] Figure 8: Prussian blue can effectively improve the survival rate of mice with severe pulmonary fibrosis;

[0038] Figure 9: Effects of Prussian blue in liver fibrosis;

[0039] Figure 10 Sirius red staining of lung tissues of mice in each group with pulmonary fibrosis treated with Prussian blue analogs, zinc Prussian blue analogs, and copper Prussian blue analogs (the second column is the enlarged image of the red circle in the first column). DETAILED DESCRIPTION

[0040] The following is a further description of specific embodiments of the present invention. It should be noted that the description of these embodiments is intended to facilitate understanding of the present invention and does not constitute a limitation of the present invention. In addition, the technical features involved in the embodiments described below may be combined with each other as long as they do not conflict with each other.

[0041] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

[0042] The "pulmonary fibrosis" mentioned in this article, also known as interstitial lung disease, is a type of disease with extremely poor prognosis that seriously affects the patient's quality of life. Its pathological characteristics are lung inflammation leading to persistent damage to the alveoli and repeated destruction, repair, reconstruction and excessive deposition of the extracellular matrix.

[0043] The "Prussian blue structure" involved in this article is a class of metal organic framework materials formed with the "Fe-CN-Fe" structure and its similar structure "M-CN-X", including Prussian blue, and analogs such as manganese Prussian blue, zinc Prussian blue, copper Prussian blue, and calcium Prussian blue. The Prussian blue structure is a face-centered cubic unit cell, composed of X ions (such as iron ions), M ions (ferrous ions) and cyanide ions, and the space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of cyanide, and the M ions are connected to the carbon atoms of cyanide, and the carbon atoms are alternately coordinated to form a cubic unit cell. The open framework structure of Prussian blue has some interstitial sites and vacancies, into which A cations (such as K) can be inserted. That is

[0044] (1) Prussian blue: The structure is a face-centered cubic unit cell, consisting of ferric ions, ferrous ions, and cyanide ions. The space group is called Fm3m. In the Prussian blue structure, the ferric ions are connected to the nitrogen atoms of the cyanide, and the ferrous ions are connected to the carbon atoms of the cyanide. The carbon atoms are coordinated alternately to form a cubic unit cell.

[0045] (2) Manganese Prussian Blue: The structure is a face-centered cubic unit cell, consisting of manganese ions, ferrous ions, and cyanide ions. The space group is called Fm3m. In the structure, the manganese ion is connected to the nitrogen atom of the cyanide.

[0046] The ferrous ions are connected to the carbon atoms of cyanide, and the carbon atoms are coordinated alternately to form a cubic unit cell.

[0047] (3) Zinc Prussian Blue: The structure is a face-centered cubic unit cell composed of zinc ions, ferrous ions, and cyanide ions. The space group is usually called Fm3m. In the Prussian blue structure, the zinc ion is connected to the nitrogen atom of the cyanide.

[0048] The ferrous ions are connected to the carbon atoms of cyanide, and the carbon atoms are coordinated alternately to form a cubic unit cell.

[0049] (4) Copper Prussian Blue: The structure is a face-centered cubic unit cell composed of copper ions, ferrous ions, and cyanide ions. The space group is usually called Fm3m. In the structure, the copper ions are connected to the nitrogen atoms of the cyanide.

[0050] The ferrous ions are connected to the carbon atoms of cyanide, and the carbon atoms are coordinated alternately to form a cubic unit cell.

[0051] Example

[0052] Example 1 Prussian blue (PB) can significantly reduce and reverse chemotherapeutic drug-induced pulmonary fibrosis

[0053] Experimental Methods: Eight-week-old C57BL / 6J mice (weighing 22-28 g) were used as experimental animals for the induction and treatment of pulmonary fibrosis. A mouse pulmonary fibrosis model was established by intratracheal instillation of bleomycin (BLM, 1 mg / kg) (model group: BLM group, 8 mice). Prussian blue (PB) was injected intratracheally into the mice on the first 2 days (i.e., 2 days before modeling) to prevent pulmonary fibrosis (prevention group: PB-BLM group, PB administration concentration of 100 μg / mL, 50 μL per mouse, 8 mice). Prussian blue was also injected intratracheally into the mice on day 14 of modeling to treat pulmonary fibrosis (treatment group: BLM-PB group, administration of the same dose as the prevention group, PB administration concentration of 100 μg / mL, 50 μL per mouse, 8 mice). At given time points (-2 days, 3 days, 7 days, 14 days, and 21 days), the lung areas of each group of mice were scanned and reconstructed using Micro-CT, and the changes in their lung parenchymal lesions were continuously observed (6 mice were randomly selected from each group, numbered, and observed continuously). 21 days after modeling, lung tissues were collected from each group of mice and lung photos were taken to record the macroscopic morphology of the lung tissue. The entire left lung tissue of the mouse was taken and fixed in 4% paraformaldehyde for more than 12 hours, then paraffin-embedded, tissue sectioned, H&E, and Masson staining were performed (8 mice were taken from each group); the right lung tissue of the mouse was taken from the fourth lobe, and monodispersed cell suspensions were prepared by tissue lysis. Single-cell sequencing was performed on the lung tissues of each group of mice (4 mice were randomly selected from each group) using a single-cell sequencing platform.

[0054] Experimental results: CT results showed (Figure 1) that before modeling, the lung tissue of mice in each group had clear vision, uniform lung parenchyma density, and natural texture; after modeling, the lung tissue of mice in the BLM group showed diffuse cloud shadows and thickened lung texture over time, that is, the degree of pulmonary fibrosis gradually worsened, and the mouse pulmonary fibrosis model was successful; no severe diffuse shadows or thick lung textures were found in the lung CT images of mice in the PB prevention (PB-BLM group) and treatment (BLM-PB group) groups, indicating that PB intervention can prevent and treat pulmonary fibrosis.

[0055] Macroscopic images of the lung tissue of mice in each group (Figure 2) showed that the lungs of mice in the normal group were pink, smooth, and free of edema. In the BLM model group, large, dark-red fibrotic lesions were observed in both the left and right lung lobes, clearly distinguishable from the surrounding tissue. The lesion area was significantly reduced in both the PB prevention (PB-BLM group) and treatment (BLM-PB group) groups compared to the BLM model group.

[0056] H&E staining of the lung tissue of mice in each group (Figure 3) showed that the lung tissue of normal mice was intact, with clear structure, uniform alveolar septa, and no obvious inflammatory cell infiltration. However, the lung tissue structure of mice in the BLM model group was significantly damaged, with disordered alveolar structure, significantly thickened alveolar septa, and significantly more inflammatory cell infiltration in the alveolar cavity than in the normal group. After PB intervention, the damage to the lung tissue structure was significantly alleviated in both the PB prevention (PB-BLM group) and treatment (BLM-PB group) groups of mice. At the same time, the alveolar structure was relatively intact, the alveolar septa were uniform, and there were fewer inflammatory cells infiltrating the alveolar cavity and septa.

[0057] Masson staining of the lung tissues of mice in each group (Figure 4) revealed that compared with the lung tissues of normal mice, the lung tissues of mice in the BLM model group showed a large accumulation of blue-stained collagen fibers, indicating significant pulmonary fibrosis. After PB intervention, the amount of collagen fibers deposited in the lung tissues of both the PB-preventive (PB-BLM group) and the PB-treated (BLM-PB group) groups was significantly reduced. H&E and Masson staining results indicate that PB intervention can reduce collagen fiber deposition in the lung tissues of mice, reduce inflammatory cell infiltration, and improve disordered alveolar structure, effectively improving pulmonary fibrosis.

[0058] Single-cell sequencing of the lung tissues of mice in each group categorized the cells within the mouse lung tissue into nine major groups, including epithelial cells, endothelial cells, fibroblasts, and mononuclear phagocytes (MPs). Further analysis of MPs, which accounted for the largest proportion of cells and showed a significant increase in number after BLM modeling, revealed that MPs could be divided into eight subpopulations, including alveolar macrophages (AlveolarMacro) and macrophages. Among them, the proportion of macrophages increased significantly in BLM-induced pulmonary fibrosis mice. However, after PB intervention (PB prevention and PB treatment), their proportions decreased significantly and approached normal levels (Figure 5).

[0059] Further analysis of the macrophage subpopulations that changed most significantly after modeling and intervention divided the macrophages into three heterogeneous subpopulations, including the Fabp5 subtype, the Selenop subtype, and the Tgfbr subtype. Among them, the Fabp5 subtype significantly increased in the lung tissue of BLM model mice, and its proportion decreased significantly after PB intervention (PB prevention, PB treatment). ECM remodeling score analysis of this group of cells showed that compared with the other two subtypes, Fabp5 subtype macrophages have a strong function of promoting pulmonary fibrosis. The tissue resident score indicated that Fabp5 subtype macrophages are bone marrow-derived cells (Figure 6). From the above results, it can be seen that PB intervention can significantly reduce the number of Fabp5 subtype macrophages that promote the progression of pulmonary fibrosis, thereby protecting or treating pulmonary fibrosis.

[0060] The origin of Fabp5 subtype macrophages was further analyzed. Through the analysis of cell interaction intensity (Figure 7A), it can be seen that Fabp5 subtype macrophages have a strong interaction with alveolar macrophages, and the effect is enhanced after BLM induction. Subpopulation subdivision of alveolar macrophages can obtain 5 cell subpopulations including the Apoe subtype. Among them, the proportion of Apoe subtype alveolar macrophages in the lung tissue of BLM model mice increased significantly, and after PB intervention (PB prevention, PB treatment), its proportion decreased significantly (Figure 7B, C). And Apoe subtype alveolar macrophages have the strongest interaction with Fabp5 subtype macrophages (Figure 7D). Therefore, it can be considered that Fabp5 subtype macrophages are recruited by Apoe subtype alveolar macrophages resident in the lung tissue. From the above results, it can be seen that PB intervention can significantly reduce the recruitment of Fabp5 subtype macrophages by Apoe subtype alveolar macrophages resident in lung tissue, which promote the progression of pulmonary fibrosis, thereby protecting or treating pulmonary fibrosis.

[0061] Example 2 Effect of PB on survival rate of severe pulmonary fibrosis

[0062] Experimental Methods: Eight-week-old C57BL / 6J mice (weighing 22-28g) were used as experimental animals for the induction and treatment of pulmonary fibrosis. A severe mouse pulmonary fibrosis model was established by intratracheal instillation of bleomycin (BLM, 1.5mg / kg) (modeling group only, 9 mice). On the first two days, Prussian Blue (PB) was injected into the mice via the airway to prevent pulmonary fibrosis (PB prevention group, PB administration concentration of 100μg / mL, 50μL per mouse, 9 mice). The survival rate of mice in each group within 21 days was calculated.

[0063] Experimental results: Severe pulmonary fibrosis can cause death in mice, with a 21-day survival rate of only 33% (6 out of 9 mice died). However, PB prevention can effectively improve the survival rate of mice, with a 21-day survival rate of 100% (0 out of 9 mice died). These results confirm that PB intervention can significantly improve the survival rate of mice with severe pulmonary fibrosis, as shown in Figure 8.

[0064] Example 3 Effect of PB on liver fibrosis in mice

[0065] Experimental Methods: Eight-week-old C57BL / 6J mice (weighing 22-28 g) were used as experimental animals for the induction and therapeutic intervention of mouse liver fibrosis. A mouse liver fibrosis model was established by subcutaneous injection of CCl4 in corn oil (50 μL / 10 g body weight, CCl4:corn oil = 1:4) to compare the therapeutic effects of Prussian blue in this model. The mice were divided into a normal group, a modeling group, and an intervention group. Two days before modeling, Prussian blue was administered once intravenously through the tail vein (PB intervention group, 200 μg / kg per mouse, six mice). Both groups (CCl4 group and PB prevention group) received subcutaneous injections of CCl4 in corn oil (50 μL / 10 g body weight, CCl4:corn oil = 1:4), while the control group received subcutaneous corn oil injections twice weekly, every three days, for six consecutive weeks. Body weight, activity, and food intake of the mice were observed weekly. Six weeks after modeling, in vivo liver ultrasound scanning, tissue sampling, Masson staining, Sirius red staining, and α-SMA immunohistochemical staining were performed to evaluate the degree of liver fibrosis.

[0066] Experimental Results: The results show that normal livers have very low collagen fiber content, while those damaged by CCl4 show a significant increase in collagen fiber deposition as determined by Masson's blue staining, and type I collagen deposition as determined by Sirius red staining. Normal livers lack α-SMA expression, while those damaged by CCl4 show high levels of α-SMA, suggesting hepatic stellate cell activation. Furthermore, intravenously administered PB treatment had no significant preventive effect on liver fibrosis. The therapeutic effect was suboptimal, as shown in Figure 9.

[0067] Example 4: Effects of Manganese Prussian Blue, Zinc Prussian Blue, and Copper Prussian Blue on Pulmonary Fibrosis

[0068] Experimental Methods: Eight-week-old C57BL / 6J mice (weighing 22-28 g) were used as experimental animals for the induction and treatment of pulmonary fibrosis. A mouse pulmonary fibrosis model (BLM group, 8 mice) was established by intratracheal instillation of bleomycin (BLM, 1 mg / kg). On day 14 of modeling, three Prussian blue analogs (manganese Prussian blue, zinc Prussian blue, and copper Prussian blue) were administered intratracheally to treat pulmonary fibrosis (referred to as the MnPB-BLM group, ZnPB-BLM group, and CuPB-BLM group, 8 mice per group). The doses of MnPB (100 μg / mL, 50 μL per mouse); ZnPB (150 μg / mL, 50 μL per mouse); and ZnPB (75 μg / mL, 50 μL per mouse) were administered, respectively. Twenty-one days after modeling, lung tissue samples were collected from each group, and lung images were taken to document macroscopic morphology. The whole lobe of the left lung tissue of the mouse was obtained and fixed with 4% paraformaldehyde for more than 12 hours, followed by paraffin embedding, tissue sectioning, and Sirius red staining.

[0069] Sirius red staining of the lung tissues of mice in each group (Figure 10) showed that the lung tissue of normal mice was intact, with a clearly visible structure and uniform alveolar septa. However, the lung tissue structure of mice in the BLM model group was significantly damaged, with disordered alveolar structure, significantly thickened alveolar septa, and a large amount of collagen fiber aggregation. After treatment with three Prussian blue analogs with Prussian blue structure, the damage to the lung tissue structure of the three groups of mice was significantly alleviated. At the same time, the alveolar structure was relatively intact, the alveolar septa were uniform, and the collagen fibers deposited in the tissues were significantly reduced. The results of Sirius red staining showed that intervention with Prussian blue analogs with Prussian blue structure can reduce collagen fiber deposition in the lung tissue of mice, improve disordered alveolar structure, and effectively improve pulmonary fibrosis.

Claims

1. A pharmaceutical composition for preventing and / or treating pulmonary fibrosis, comprising a substance having a Prussian blue structure. The Prussian blue structure is a face-centered cubic unit cell composed of X ions, M ions, and cyanide ions, with a space group generally referred to as Fm3m. In the Prussian blue structure, the X ions are linked to the nitrogen atoms of the cyanide, and the M ions are linked to the carbon atoms of the cyanide, with the carbon atoms alternately coordinated to form a cubic unit cell. Cations A are inserted into interstitial sites and vacancies in the open framework structure of the Prussian blue. in, A is selected from one or more cations of NH4, Li, Na, K, preferably K and / or Na; X is selected from one or more combinations of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag, and Gd metal ions, preferably Fe, Mn, and / or Zn; M is selected from one or more transition metal ions having variable valence among Mn, Fe, and Co, preferably Fe and / or Co.

2. The pharmaceutical composition according to claim 1, further comprising other active ingredients for treating pulmonary fibrosis, wherein the active ingredients for treating pulmonary fibrosis are selected from glucocorticoids, immunosuppressants, pirfenidone and / or nintedanib.

3. Use of a substance having a Prussian blue structure in the preparation of a medicament for preventing and / or treating pulmonary fibrosis, wherein the Prussian blue structure is a face-centered cubic unit cell composed of X ions, M ions, and cyanide ions, with a space group generally referred to as Fm3m. In the Prussian blue structure, the X ions are linked to the nitrogen atoms of the cyanide, and the M ions are linked to the carbon atoms of the cyanide, with the carbon atoms alternately coordinated to form a cubic unit cell. Cations A are inserted into interstitial sites and vacancies in the open framework structure of the Prussian blue. in, A is selected from one or more cations of NH4, Li, Na, K, preferably K and / or Na; X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag, and Gd, preferably Fe, Mn and / or Zn; M is selected from one or more transition metal ions having variable valence among Mn, Fe, and Co, preferably Fe and / or Co.

4. The method of claim 3, wherein the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.

5. A pharmaceutical composition comprising a substance having a Prussian blue structure and bleomycin, wherein the substance having a Prussian blue structure can alleviate the side effects of pulmonary fibrosis caused by bleomycin. The Prussian blue structure is a face-centered cubic unit cell, composed of X ions, M ions and cyanide ions, and the space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, and the M ions are connected to the carbon atoms of the cyanide. The carbon atoms are alternately coordinated to form a cubic unit cell, and the cation A is inserted into the interstitial sites and vacancies of the open framework structure of Prussian blue. in, A is selected from one or more cations of NH4, Li, Na, K, preferably K and / or Na; X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag, and Gd, preferably Fe, Mn and / or Zn; M is selected from one or more transition metal ions having variable valence among Mn, Fe, and Co, preferably Fe and / or Co.

6. The composition of claim 5, wherein the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.

7. Use of a substance having a Prussian blue structure in the preparation of a preparation for reducing the side effects of bleomycin, wherein the side effect of bleomycin is the effect of bleomycin-induced pulmonary fibrosis. The Prussian blue structure is a face-centered cubic unit cell, composed of X ions, M ions and cyanide ions, and the space group is usually called Fm3m. In the Prussian blue structure, the X ions are connected to the nitrogen atoms of the cyanide, and the M ions are connected to the carbon atoms of the cyanide. The carbon atoms are alternately coordinated to form a cubic unit cell, and the cation A is inserted into the interstitial sites and vacancies of the open framework structure of Prussian blue. in, A is selected from one or more cations of NH4, Li, Na, K, preferably K and / or Na; X is selected from one or more metal ions of Ca, Sr, Ba, Mn, Fe, Co, Ni, Cu, In, Ir, Nb, Pd, Ag, and Gd, preferably Fe, Mn and / or Zn; M is selected from one or more transition metal ions having variable valence among Mn, Fe, and Co, preferably Fe and / or Co.

8. The method of claim 7, wherein the substance having a Prussian blue structure is selected from one or more of Prussian blue, manganese Prussian blue, zinc Prussian blue, and copper Prussian blue.