CN114344316A - Application of platycodin D in treating acute lung injury caused by viral pneumonia - Google Patents
Application of platycodin D in treating acute lung injury caused by viral pneumonia Download PDFInfo
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- CN114344316A CN114344316A CN202210067295.9A CN202210067295A CN114344316A CN 114344316 A CN114344316 A CN 114344316A CN 202210067295 A CN202210067295 A CN 202210067295A CN 114344316 A CN114344316 A CN 114344316A
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Abstract
The invention relates to application of platycodin D in treating acute lung injury caused by viral pneumonia. According to the invention, a severe infection mouse model induced by influenza virus infection is established, the application of platycodin D in treating acute lung injury caused by viral pneumonia is explored, and the survival rate of the severe infection mouse model induced by PR8 infection can be obviously improved by the platycodin D, and lung injury caused by infection is obviously relieved. The invention also observes the effect of platycodin D on the secretion of proinflammatory factors and inflammation-inhibiting factors of Raw264.7 cells induced by R837, mouse primary abdominal cavity macrophages and mouse macrophages directly infected by influenza virus PR 8. The invention has the beneficial effects that: provides an effective medicine for treating acute lung injury caused by viral pneumonia, especially severe viral pneumonia cases.
Description
Technical Field
The invention relates to the field of biological medicines, in particular to application of platycodin D in treatment of acute lung injury caused by viral pneumonia.
Background
Viral pneumonia refers to inflammatory pathological changes of lung caused by virus infection, and common pathogenic viruses include influenza virus, parainfluenza virus, adenovirus, coronavirus, rhinovirus, respiratory syncytial virus, measles virus and the like. The outbreak or the epidemic is more prevalent in the winter and spring. Patients and latent patients are main infection sources, most of the patients are transmitted by air droplets, contact and other ways, and people with normal or abnormal immune functions are generally susceptible. In recent years, due to the continuous emergence of SARS coronavirus, avian influenza virus, novel coronavirus and the like, the viral pneumonia has a high mortality rate, and becomes an important disease in the public health field worldwide.
Acute Lung Injury (ALI) refers to Acute hypoxic respiratory insufficiency or respiratory failure caused by diffuse pulmonary interstitial and alveolar edema caused by injury of pulmonary capillary endothelial cells and alveolar epithelial cells in the process of non-cardiogenic diseases such as severe infection, shock, trauma and burn, and Acute Respiratory Distress Syndrome (ARDS) can appear after the injury to a certain degree, and the death rate is high.
Acute lung injury can be caused by various clinical diseases, wherein viral pneumonia is one of the direct factors causing acute lung injury.
Platycodin D (PD) is a triterpene monomer extracted from radix Platycodi57H92O28The structural formula is as follows:
research shows that the medicine has various pharmacological effects of resisting inflammation, reducing blood sugar and blood fat, resisting tumor, regulating immunity, resisting allergy and the like, and has killing effect on various tumor cells of skin cancer, human leukemia, ovarian cancer, breast cancer, colorectal cancer and the like.
In the literature (i.e., research on the mechanism of protecting acute lung injury by inhibiting apoptosis through Bax/Bcl-2/Caspase-3 signaling pathway [ J ]. world science and technology-modernization of traditional Chinese medicine ]) platycodin D has been reported to have a protective effect on lipopolysaccharide-induced acute lung injury in rats, and the action mechanism of the platycodin D is closely related to inhibition of Bax/Bcl-2/Caspase-3 signaling pathway and reduction of apoptosis of lung tissue cells. However, no report of the application of platycodin D in the treatment of acute lung injury caused by viral pneumonia is found at present.
Disclosure of Invention
The invention aims to provide a new application of platycodin D aiming at the defects in the prior art.
In a first aspect, the invention provides the use of platycodin D in the manufacture of a medicament for treating acute lung injury caused by viral pneumonia, or for reducing the mortality rate of severe viral pneumonia.
In one embodiment of the present invention, the viral pneumonia is caused by influenza virus, coronavirus, parainfluenza virus, adenovirus, rhinovirus, respiratory syncytial virus or measles virus.
In a preferred embodiment, the viral pneumonia is caused by influenza virus PR 8.
As another embodiment of the present invention, the platycodin D is used as the only active ingredient; or the medicament further comprises an active ingredient other than platycodin D, wherein the active ingredient is effective for acute lung injury caused by viral pneumonia or reduction of severe mortality of viral pneumonia.
In a second aspect, the invention provides a pharmaceutical composition for treating acute lung injury caused by viral pneumonia or reducing severe mortality of viral pneumonia, wherein the pharmaceutical composition contains platycodin D and a conventional pharmaceutical carrier.
As an embodiment of the present invention, the platycodin D is used as the only active ingredient of the pharmaceutical composition; or the pharmaceutical composition further comprises an active ingredient other than platycodin D, which is effective in treating acute lung injury caused by viral pneumonia or reducing severe mortality of viral pneumonia.
As a preferred embodiment, the conventional pharmaceutical carriers are selected from the group consisting of diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants.
As another embodiment of the present invention, the pharmaceutical composition is in oral, topical or injectable dosage form.
In a third aspect, the present invention provides the use of platycodin D in the preparation of an experimental reagent for:
a) reducing the secretion of proinflammatory cytokines IL-6 and TNF-alpha and human macrophage chemotactic protein MCP-1, I type interferon IFN-beta in Raw264.7 cells induced by R837 and promoting the secretion of inflammatory cytokine IL-10 in Raw264.7 cells induced by R837;
b) the secretion of proinflammatory cytokines IL-6 and TNF-alpha and human macrophage chemotactic protein MCP-1 and I type interferon IFN-beta in R837-induced mouse primary abdominal cavity macrophages is reduced, and the secretion of inflammatory cytokine IL-10 in R837-induced mouse primary abdominal cavity macrophages is promoted; and/or
c) Inhibit the secretion of proinflammatory cytokines IL-6 and TNF-alpha in primary abdominal cavity macrophages of mice infected by influenza virus PR 8.
The invention has the advantages that:
viral pneumonia is an acute respiratory infectious disease caused by infectious virus infection of different degrees, and after a human body is infected by viruses, acute lung injury of systemic inflammatory reaction caused by cytokine storm can be induced, so that an effective prevention and treatment means is always lacking in clinic at present. The traditional Chinese medicine has the advantages of dialectical treatment, immunoregulation, symptom improvement and high safety, and accumulates abundant experience for preventing and treating viral pneumonia, so that active substances with potential treatment effects on different pathological processes of viral pneumonia need to be searched from the traditional Chinese medicine, and scientific basis is provided for clinical application of the traditional Chinese medicine.
According to the invention, a severe infection mouse model induced by influenza virus infection is established, the application of platycodin D in treating acute lung injury caused by viral pneumonia is explored, and the survival rate of the severe infection mouse model induced by PR8 infection can be obviously improved by the platycodin D, and lung injury caused by infection is obviously relieved. The platycodin D is an effective medicine for treating acute lung injury caused by viral pneumonia caused by influenza virus or reducing severe viral pneumonia death rate caused by the influenza virus. Meanwhile, since the 2019 novel coronavirus (2019-nCoV) and the like and the influenza virus are single-stranded RNA viruses, a cytokine storm induced by viral infection is a pathological basis for causing malignant transformation of diseases, and therefore, the platycodin D is effective to lung injury caused by the 2019-nCoV and the like.
The invention also utilizes R837 to stimulate mouse macrophage cell line Raw264.7 cells to construct a macrophage model infected by influenza virus, and finds that platycodin D plays a role in bidirectional regulation and control on proinflammatory factors and inflammation-inhibiting factors; the regulation and control effect of platycodin D on an R837 induced inflammatory factor is also confirmed in primary abdominal cavity macrophages of mice, and the bidirectional regulation and control effect on a proinflammatory factor and an inflammation-inhibiting factor is also found; the influenza virus PR8 is also utilized to directly infect mouse macrophages in vitro to construct a real influenza virus infected macrophage model, and the platycodin D is found to be capable of obviously inhibiting the secretion of proinflammatory cytokines induced by the infection of the influenza virus PR8 in the mouse primary abdominal cavity macrophages. The results indicate that the platycodin D can be used for preparing an experimental reagent for researching the generation and development mechanism of the viral pneumonia caused by the influenza virus.
Drawings
FIG. 1: effect of PD on body weight and survival days in severe infection models induced by influenza PR8 infection.
FIG. 2 is a drawing: effect of PD on pulmonary index in severe infection model induced by influenza PR8 infection.
FIG. 3: cytotoxicity of PD on RAW264.7 cells.
FIG. 4 is a drawing: the PD has effects on proinflammatory cytokines IL-6 and TNF-alpha, human macrophage chemotactic protein MCP-1, type I interferon IFN-beta and inflammatory cytokine IL-10 in Raw264.7 cells induced by R837.
FIG. 5: the influence of PD on proinflammatory cytokines IL-6 and TNF-alpha, human macrophage chemotactic protein MCP-1, type I interferon IFN-beta and inflammatory cytokine IL-10 in R837-induced mouse primary abdominal cavity macrophages is inhibited.
FIG. 6: the PD has a regulating effect on macrophage inflammatory reaction caused by infection of influenza virus PR 8.
Detailed Description
The following detailed description of the present invention will be made with reference to the accompanying drawings.
Example 1
The method comprises the following steps:
influenza virus PR8 infection induced severe infection model establishment, 72C 57BL mice were adaptively fed for one week and divided into normal group (12) and construction group (60) according to random distribution method. The preparation method of the model comprises the following steps: the mice are sucked by a 100 mu l pipette under mild anesthesia with isoflurane inhalation, and are inoculated with a model through a nasal cavity, PBS of a normal group, OSV (30mg/kg) of a model group PR8, PR8+ positive drug group OSV (30mg/kg), PD of a PR8+ drug group (low dose: 1mg/kg, medium dose: 2mg/kg and high dose: 4mg/kg) are administrated two hours after the model is made, the Day of the model making is Day0, the mice are subjected to gastric lavage administration according to the weight of the mice, the weight of the mice is continuously observed after 7 days of continuous administration, the Day 14 is continuously observed, and the daily weight change condition of the mice is recorded. At the same time, a 20% weight loss above the initial body weight was set as the humane endpoint. In order to explore the protective effect of PD on the lung of mice infected by influenza virus PR8, the lung of each group of mice was picked on the 14 th day after infection, and the lung index was calculated.
Results and conclusions: lethal dose of influenza virus PR8(2 x 10)5PFU/mL) could lead to total death within 8 days of the mice, and PD treatment increased survival of the mice by 67% (figure 1). The experimental results show that the survival rate of the PR8 infected mouse can be remarkably improved by the PD, and the in-vivo protection effect on the PR8 infected mouse is achieved. The PD can obviously inhibit the lung index of the mice infected by the influenza virus PR8, and the PD plays a role in protecting the lungs of the mice infected by the influenza virus PR8 and can obviously relieve the lung injury caused by the infection of the influenza virus PR8 (figure 2).
Example 2
The method comprises the following steps: uniformly inoculating RAW264.7 cells into a 96-well plate, and culturing in a 37-degree cell culture box for 24h, 48h and 72 h. Then, 10. mu.L of PD at various concentrations was added to the plate, 10. mu.L of LCCK8 solution was added to each well of the 96-well plate using the same pipette, and after incubating the 96-well plate in an incubator for 4 hours, cytotoxicity was detected by measuring absorbance at 450nm using a microplate reader.
Results and conclusions: it was found that PD below 10 μ M showed no significant cytotoxicity and above 10 μ M cytotoxicity was observed at different incubation times (fig. 3).
Example 3
The method comprises the following steps: influenza viruses are single-stranded RNA viruses. Imiquimod (R837) is an artificially synthesized single-stranded RNA that can mimic influenza virus nucleic acid, which is also a single-stranded RNA, in vitro. Therefore, we first constructed an influenza virus-infected macrophage model using R837 to stimulate mouse macrophage cell line raw264.7 cells.
Results and conclusions: PD (1.25, 2.5, 5 or 10mM) significantly reduced the secretion of proinflammatory cytokines IL-6, TNF-alpha, human macrophage chemotactic protein MCP-1, type I interferon IFN-beta in Raw264.7 cells induced by R837(5mg/mL), and simultaneously promoted the secretion of the anti-inflammatory cytokine IL-10 induced by R837 (FIG. 4).
Example 4
The method comprises the following steps: the regulation and control effect of PD on R837-induced inflammatory factors is further confirmed in primary abdominal cavity macrophages of mice.
Results and conclusions: PD shows similar anti-inflammatory activity in primary abdominal cavity macrophages of mice, can obviously reduce proinflammatory cytokines IL-6 and TNF-alpha induced by R837, inhibit the secretion of human macrophage chemotactic protein MCP-1, type I interferon IFN-beta, and simultaneously promote the secretion of the anti-inflammatory cytokines IL-10 induced by R837 (figure 5).
Example 5
The method comprises the following steps: the influenza virus PR8 directly infects mouse macrophages in vitro to construct a real influenza virus infected macrophage model.
Results and conclusions: the regulation and control effect of PD on macrophage inflammatory reaction caused by influenza virus PR8 infection is shown in figure 6, and PD can obviously inhibit secretion of proinflammatory cytokines IL-6 and TNF-alpha induced by influenza virus PR8 infection in primary abdominal cavity macrophages of mice.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (9)
1. The application of platycodin D in preparing the medicine is characterized in that the medicine is used for treating acute lung injury caused by viral pneumonia or reducing the death rate of severe viral pneumonia.
2. The use according to claim 1, wherein the viral pneumonia is caused by influenza virus, coronavirus, parainfluenza virus, adenovirus, rhinovirus, respiratory syncytial virus or measles virus.
3. The use of claim 2, wherein the viral pneumonia is caused by influenza virus PR 8.
4. The use according to claim 1, wherein platycodin D is used as the sole active ingredient; or the medicament further comprises an active ingredient other than platycodin D, wherein the active ingredient is effective for acute lung injury caused by viral pneumonia or reduction of severe mortality of viral pneumonia.
5. A pharmaceutical composition for treating acute lung injury caused by viral pneumonia or reducing severe viral pneumonia mortality, which is characterized by comprising platycodin D and a conventional pharmaceutical carrier.
6. The pharmaceutical composition according to claim 5, wherein platycodin D is used as the only active ingredient of the pharmaceutical composition; or the pharmaceutical composition further comprises an active ingredient other than platycodin D, which is effective in treating acute lung injury caused by viral pneumonia or reducing severe mortality of viral pneumonia.
7. The pharmaceutical composition according to claim 5, wherein the conventional pharmaceutical carriers are selected from the group consisting of diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants.
8. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in an oral, topical or injectable dosage form.
9. Application of platycodin D in preparation of an experimental reagent, which is characterized in that the experimental reagent is used for:
a) reducing the secretion of proinflammatory cytokines IL-6 and TNF-alpha and human macrophage chemotactic protein MCP-1, I type interferon IFN-beta in Raw264.7 cells induced by R837 and promoting the secretion of inflammatory cytokine IL-10 in Raw264.7 cells induced by R837;
b) the secretion of proinflammatory cytokines IL-6 and TNF-alpha and human macrophage chemotactic protein MCP-1 and I type interferon IFN-beta in R837-induced mouse primary abdominal cavity macrophages is reduced, and the secretion of inflammatory cytokine IL-10 in R837-induced mouse primary abdominal cavity macrophages is promoted; and/or
c) Inhibit the secretion of proinflammatory cytokines IL-6 and TNF-alpha in primary abdominal cavity macrophages of mice infected by influenza virus PR 8.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115969976A (en) * | 2022-07-11 | 2023-04-18 | 浙江大学 | Application of FBXO6 protein or coding gene thereof as target spot |
| WO2024032527A1 (en) * | 2022-08-08 | 2024-02-15 | 石药集团中奇制药技术（石家庄）有限公司 | Use of compound containing tricyclic heteroaryl |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104161765A (en) * | 2014-08-22 | 2014-11-26 | 上海交通大学医学院 | Application of platycodin D in preparing medicaments for inhibiting angiogenesis |
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2022
- 2022-01-20 CN CN202210067295.9A patent/CN114344316A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104161765A (en) * | 2014-08-22 | 2014-11-26 | 上海交通大学医学院 | Application of platycodin D in preparing medicaments for inhibiting angiogenesis |
Non-Patent Citations (3)
| Title |
|---|
| LING LI等: "Study on the inhibition of PLD on IAV-induced pulmonary macrophage based on autophagy and apoptosis" * |
| WEIWEI TAO等: "Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro" * |
| YONGCAN WU等: "Suppression of NLRP3 inflammasome by Platycodin D via the TLR4/MyD88/NF-κB pathway contributes to attenuation of lipopolysaccharide induced acute lung injury in rats" * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115969976A (en) * | 2022-07-11 | 2023-04-18 | 浙江大学 | Application of FBXO6 protein or coding gene thereof as target spot |
| CN115969976B (en) * | 2022-07-11 | 2023-12-08 | 浙江大学 | Application of FBXO6 protein or encoding gene thereof as target point |
| WO2024032527A1 (en) * | 2022-08-08 | 2024-02-15 | 石药集团中奇制药技术（石家庄）有限公司 | Use of compound containing tricyclic heteroaryl |
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