CN114159420A - Application of acetylshikonin in preparation of anti-lung inflammatory factor storm medicine - Google Patents
Application of acetylshikonin in preparation of anti-lung inflammatory factor storm medicine Download PDFInfo
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Abstract
The invention relates to an application of a compound acetylshikonin in preparing a medicine for resisting a lung inflammatory factor storm, namely an inhibition effect of the acetylshikonin on mouse acute lung injury and an inflammatory factor storm induced by polyinosinic acid and SARS-CoV-2 spinous process protein. The compound acetylshikonin can inhibit polyinosinic acid and inflammatory factor induced by SARS-CoV-2 spinous process protein, and obviously inhibit interleukin IL-6,
，
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of acetylshikonin in preparation of a medicine for resisting a lung inflammatory factor storm.
Background
The cytokine storm (cytokine storm) refers to the phenomenon that a plurality of cytokines such as TNF-alpha, IL-1, IL-6, IL-12, IFN-alpha, IFN-beta, IFN-gamma, MCP-1, IL-8 and the like in body fluid are rapidly and massively generated after an organism is infected with microorganisms, and is an important reason for causing acute respiratory distress syndrome and multi-organ failure.
Pneumonia is one of the international common epidemic diseases and is a public health problem threatening the health of people in the world, the first symptoms are mainly shortness of breath, dyspnea, fever and cough, and severe patients can cause severe respiratory syndrome, renal failure and even death. Pneumonia mainly includes viral pneumonia, bacterial pneumonia and mycoplasma pneumonia. The viral pneumonia such as coronavirus has the characteristics of long incubation period, strong infectivity and the like, so that great economic loss is caused to social safety and human health. However, at present, no specific therapy exists for the novel coronavirus to the cell inflammatory factor storm generated by the organism, so that the safe and efficient anti-inflammatory treatment and prevention method has important significance for treating the novel pneumonia patients.
Chinese herbal medicine plays an important role in the prevention and treatment of pneumonia. The acetylshikonin is a natural compound and is an important component in arnebia euchroma (Royle) Johnst, a Chinese herbal medicine. Lithospermum erythrorhizon belongs to perennial herb of Boraginaceae, and has antibacterial, antiviral, and antitumor effects. The acetylshikonin is used as the effective component of main monomer of arnebia euchroma, is naphthoquinone pigment compound produced by large-scale culture of arnebia euchroma cells, and has strong anti-inflammatory activity. At present, no report about the application of the acetylshikonin in resisting the lung inflammatory factor storm exists, namely, no research shows that the acetylshikonin has the function of treating the cell inflammatory factor storm.
Disclosure of Invention
The invention aims to overcome the limitation and urgency of the existing novel clinical treatment of coronary pneumonia, and provides a new application of acetylshikonin in preparing a medicine for resisting lung inflammatory factor storm. The invention is found by experiments that: the acetylshikonin can inhibit polyinosinic acid Poly (I: C) and spinous process protein (SARS-CoV-2) in vivo to induce cell inflammatory factor storm and lung injury caused by virus infection, provides an effective medicine for improving acute respiratory distress syndrome for clinical research, and can be applied to develop a specific medicine for human pneumonia for inducing acute respiratory distress syndrome.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a new application of acetylshikonin in preparing a medicine for resisting lung inflammatory factor storm.
Compound Acetylshikonin (Acetylshikonin, molecular formula: C)18H18O6Molecular weight: 330.3), the structural formula is shown as follows:
the application can be further the application of the acetylshikonin in preparing the medicine for treating viral pneumonia, bacterial pneumonia and mycoplasma pneumonia. The application emphasizes that the anti-inflammatory effect of the acetylshikonin in acute respiratory distress syndrome caused by viral pneumonia, bacterial pneumonia, mycoplasma pneumonia and the like can realize the obvious effect on preventing and treating pneumonia by reducing the phenomena of severe acute respiratory distress syndrome, regulating the expression of IL-6, IL-10 and the like.
Furthermore, in the application, the acetylshikonin can inhibit inflammatory factor storm reaction of polymyosylate and SARS-CoV-2 spinous process protein in mouse lung.
Furthermore, in the application, the acetylshikonin can relieve acute lung injury caused by polymyosylate and SARS-CoV-2 spinous process protein in mouse lung tissues.
Specifically, the in vitro dosage of the acetylshikonin is 2.5-10 mu M, and the in vivo dosage is 100-300 mg/kg. Further, acetylshikonin was able to inhibit the production of polyinosinic-induced macrophage IL-6 at concentrations of 2.5, 5 and 10. mu.M. When the concentration of the acetylshikonin is 100 and 300mg/kg, the acetylshikonin can obviously inhibit the mouse lung inflammation factor storm caused by polyinosinic acid and SARS-CoV-2 spinous process protein, namely can inhibit the activity of the polyinosinic acid and SARS-CoV-2 spinous process protein induced inflammation storm factor in a mouse acute lung injury model, and can obviously inhibit the mouse lung injury caused by polyinosinic acid and SARS-CoV-2 spinous process protein.
Specifically, the administration mode of the acetylshikonin is oral administration, gastric lavage, intraperitoneal injection or aerosol inhalation. The acetylshikonin can be applied to the activity of inflammatory factors of anti-lung inflammation storm medicines.
The poly-sarcosine and the recombinant SARS-CoV-2 spinous process protein can cause acute lung injury of mice in a small animal model, can simulate the storm symptoms of inflammatory factors which are mainly characterized by IL-6, TNF alpha and IL-1 alpha, can effectively induce infiltration and activation of neutrophilic granulocyte, monocyte and macrophage to the lung, generate acute lung injury and simulate the lung inflammation symptoms caused by severe COVID-19.
The invention mainly applies to acetylshikonin to reduce severe acute respiratory distress syndrome and regulate the expression of IL-6, TNF alpha and IL-1 alpha. The application emphasizes that the anti-cell inflammatory factor storm effect of the acetylshikonin is not only suitable for viral pneumonia, bacterial pneumonia and mycoplasma pneumonia, but also suitable for cell inflammatory factor storm caused by other diseases. The research of the invention finds that: the acetylshikonin can be used as inhibitor of inflammatory factor storm reaction caused by polyinosinic acid and SARS-CoV-2 spinous process protein in mouse lung.
Acute Respiratory Distress Syndrome (ARDS) is the first cause of death of patients with acute SRAS-CoV-2, SRAS-CoV, MERS and H1N1 virus infection, the current supportive treatment for patients mainly comprises lung ventilation and hormone treatment, no targeted drugs for different virus infections exist, and the mechanism of ARDS caused by virus infection is not clear enough. The research on the medicine capable of inhibiting the ARDS caused by acute viral infection in an animal model can provide a research basis for clinical and scientific researchers. A method of using acetylshikonin to inhibit acute respiratory distress syndrome inflammatory storm of polyinosinic acid and SARS-CoV-2 spike protein comprising the steps of:
the mice are treated by 100 or 300mg/kg acetylshikonin for 3 days for 1 time/day through intragastric administration, after the abdominal anesthesia, placing the mouse on an operation table, stripping the trachea, injecting mixed solution of polyinosinic acid and SARS-CoV-2 spinous process protein, the injection volume is not more than 40 μ L, sealing the mouse throat wound with surgical suture after injection, mice injected with the same volume and dose of a premixed solution of polyinosinic acid and SARS-CoV-2 spinous process protein served as controls, wherein the pre-mixed solution of poly-sarcosine and SARS-CoV-2 spinous process protein is injected, the dosage of the polyinosinic acid is 2.5mg/kg, the injection amount of the SARS-CoV-2 spinous process protein is 15 mug, after 6 hours of injection, it was determined whether acetylshikonin could inhibit the inflammatory storm in mice by analysis of inflammatory factors in the lavage fluid of the mouse lungs. The method is used for detecting the influence of the acetylshikonin on the cell inflammatory factors in vitro and in vivo.
Compared with the prior art, the invention has the following beneficial effects:
the acetylshikonin can inhibit cell inflammation factor storm caused by polyinosinic acid Poly (I: C) in vitro, and Poly (I: C) and SARS-CoV-2 spinous process protein can induce ARDS caused by virus infection in a mouse model. The acetylshikonin can inhibit polyinosinic acid Poly (I: C) and SARS-CoV-2 spinous process protein in vivo from inducing cell inflammatory factor storm and lung injury caused by virus infection, provides an effective medicine for improving acute respiratory distress syndrome for clinical scientific research, and provides guidance for developing specific medicines for inducing human pneumonia such as SRAS-CoV-2 and the like of the acute respiratory distress syndrome.
Drawings
FIG. 1 shows the inhibition of polyinosinic acid-induced macrophage IL-6 secretion by acetylshikonin, and the results in FIG. 1 show that: compared with DMSO group, 2.5-10 μ M acetylshikonin can remarkably inhibit macrophage RAW264.7 from secreting verification factor IL-6 after treating macrophage RAW264.7 of mouse;
FIG. 2 shows the effect of acetylshikonin at concentrations of 100(A) and 300(B) mg/kg on the inhibition of polyinosinic acid and SARS-CoV-2 spike protein-induced cytokines storm IL-6, TNF α and IL-1 α; in FIG. 2, A shows: mice treated by 100mg/kg of acetylshikonin through intragastric administration can obviously reduce the activities of verification factors IL-6, TNF alpha and IL-1 alpha; in FIG. 2, B shows: the mice treated by 300mg/kg of acetylshikonin through intragastric administration can obviously reduce the concentrations of inflammatory factors IL-6, TNF alpha and IL-1 alpha;
FIG. 3 shows HE results of lung tissues of mice at concentrations of acetylshikonin of 100(A) and 300(B) mg/kg; the results show that: the acetylshikonin can obviously inhibit the lung injury caused by acute respiratory distress syndrome of mice induced by Poly (I: C) and SARS-CoV-2 spinous process protein. In FIG. 3, A shows: compared with a control group, the pulmonary alveolar space broadening degree of the experimental group treated by 100mg/kg is reduced, the interstitial congestion edema is reduced, the pulmonary alveolar space is broadened, and the small airway injury is weakened; in FIG. 3, B shows: compared with the control group, the experimental group treated by 300mg/kg has reduced alveolar septal broadening, interstitial hyperemia and edema, widened alveolar space and weakened small airway injury.
Detailed Description
The technical solution of the present invention is further described in detail below, but the scope of the present invention is not limited thereto.
Example (b):
materials and methods
1 Material
1.1.1 Acetylshikonin
The acetylshikonin used in the invention is purchased from ChemFaces of Wuhan and has the purity of 97%.
1.1.2 reagents and cells
DMEM medium and FBS were purchased from BI corporation,
RAW264.7 cells were purchased from Beijing Korea Biotech Ltd,
poly (I: C) was purchased from Invivogen,
SARS-CoV-2 spinous process protein was purchased from Kinsley,
BALB/c mice were purchased from Witongli Inc.,
LEGENDplexTMmouse cytokine detection kit was purchased from Biolegend,
erythrocyte lysates were purchased from solibao corporation.
1.1.3 instruments and apparatus
Microplate reader (BD corporation); inverted microscope (OLYPUMS);
haier medical low-temperature storage box (Qingdao haier special electric appliance limited);
analytical balance (mertler-toledo instruments shanghai ltd);
a Thermo clean bench; IVC systems (von experimental animal facilities ltd, suzhou);
a pipette gun, a pipette (the specification is respectively 5ml, 10ml and 25ml) and a centrifuge tube (the specification is respectively 15ml/50 ml); 6-well plate, 96-well plate (Corning Corp.);
micro-injection needles (Hamilton); electronic balances (mertler-toledo instruments shanghai ltd);
haier medical low-temperature storage box (Qingdao haier special electric appliance limited);
flow cytometry (BD FACS Calibur).
2.1.1 cell culture and cytokine Activity detection:
culture of mouse macrophage RAW264.7 the medium used was DMEM + 10% by volume FBS + 1% by volume streptomycin diabody. Mouse macrophages were seeded in 12-well plates at 6 × 10 cells per well51mL of culture medium per well, after 24h of attachment, cells were treated with 1mL of Poly (I: C) containing 10. mu.g/mL, and DMSO or acetylshikonin (2.5, 5 and 10. mu.M) culture medium, DMSO group was used as a negative control, and the conditions of intracellular active factors IL-6, TNF-. alpha.and IL-1. alpha. were then examined after 12h, and the detailed results are shown in FIG. 1.
The results indicate that: compared with DMSO group, 2.5-10 μ M acetylshikonin can significantly inhibit macrophage RAW264.7 from secreting verification factor IL-6 after treating macrophage RAW264.7 of mouse.
2.1.2 establishment of mouse Virus infectivity ARDS model and alveolar lavage fluid cytokine analysis
BALB/c male mice 8 weeks old were divided into 4 groups of 5 mice each, control group, acetylshikonin 100mg/kg group and acetylshikonin 300mg/kg group.
A, control group drug: DMSO 10% + PEG 40045% + 45% H2O, 1mL control drug contained 100. mu.L DMSO, 450. mu.L PEG400, and 450. mu.L water.
B, 100mg/kg acetylshikonin drug: DMSO 10% + PEG 40045% + 45% H containing acetylshikonin2O, a mixture of 100. mu.L of acetylshikonin and DMSO (prepared by adding 33.3. mu.L of 300mg/mL acetylshikonin to 66.7. mu.L DMSO), 450. mu.L of PEG400 and 450. mu.L of water to 1mL of the drug.
C, 300mg/kg acetylshikonin drug: DMSO 10% + PEG 40045% + 45% H containing acetylshikonin2O, namely 1mL of the medicine contains 100 mu L of mixed solution of the acetylshikonin and DMSO, 450 mu L of PEG400 and 450 mu L of water, wherein the concentration of the acetylshikonin is 300 mg/mL.
Respectively administering corresponding drugs to mice of a control group, an acetylshikonin 100mg/kg group and an acetylshikonin 300mg/kg group for 3d, performing intragastric administration with 10 mu L/g of the weight of the mice every day, performing intraperitoneal injection of avermectin for anesthesia 2h after the 3d intragastric treatment, placing the mice on an operation table, carefully opening the skin above the trachea of the mice with scissors, separating muscles near the trachea with tweezers and stripping the trachea, injecting a premixed solution of Poly (I: C) and SARS-CoV-2 spinous process protein through the trachea injection, wherein the injection amount of Poly (I: C) is 2.5mg/kg of the mice, the injection amount of SARS-CoV-2 spinous process protein is 15 mu g per mouse, the injection volume of the premixed solution is not more than 50 mu L to prevent the mice from dry drowning water, closing the throat wounds of the mice with surgical operation sutures after the injection is completed, the treatment groups were designated Poly (I: C), acetylshikonin 100mg/kg and 300mg/kg, respectively. Poly (I: C) and SARS-CoV-2 spinous process protein 6 hours after establishing a mouse virus infectious ARDS model, after the mouse is anesthetized by intraperitoneal Avermectin injection, the mouse trachea is stripped by scissors and tweezers, a 26G medical vein indwelling needle is inserted into the mouse trachea, the hard needle head of the vein indwelling needle is removed, a syringe filled with 1mL of physiological saline is connected to the indwelling needle, the syringe is slowly injected into the trachea and alveoli, then liquid is slowly pumped back, lavage is repeated three times, and the liquid pumped back for the first time is used for cell subset identification and cytokine analysis of alveolar lavage fluid.
Centrifuging the alveolar lavage fluid sample taken for the first time to obtain supernatant, analyzing the cytokine by using a multi-cytokine detection kit, operating according to the kit specification, detecting the inflammatory related cytokine of the mouse by using a flow cytometer, and analyzing the experimental result by using analytical software LEGENDplex v8.0 matched with the kit, wherein the result is shown in figure 2.
In FIG. 2, A shows: mice treated by 100mg/kg of acetylshikonin through intragastric administration can obviously reduce the activities of verification factors IL-6, TNF alpha and IL-1 alpha; in FIG. 2, B shows: mice treated by 300mg/kg acetylshikonin gavage can obviously reduce the concentration of inflammatory factors IL-6, TNF alpha and IL-1 alpha.
2.1.3 Lung tissue acquisition, fixation and hematoxylin-eosin staining detection of mouse Virus infectious ARDS model
Respectively administering corresponding drugs to mice of a control group, an acetylshikonin 100mg/kg group and an acetylshikonin 300mg/kg group for intragastric administration for 3d, after the intragastric administration for 2h is finished, injecting avermectin into the abdominal cavity for anesthesia, the mice were placed on a console, the skin covered on the thyroid gland of the mice was carefully opened with scissors, the muscles near the trachea were separated with forceps and the trachea was stripped off, a premixed solution of Poly (I: C) and SARS-CoV-2 spinous process protein was injected through the trachea at an injection rate of 2.5mg/kg mice, the amount of SARS-CoV-2 spinous process protein was 15. mu.g per mouse, the injection volume of the premixed solution was not more than 50. mu.L to prevent dry drowning in the mice, and the throat wounds of the mice were closed with surgical sutures after the injection was completed, which were designated as Poly (I: C) group, acetylshikonin 100mg/kg and 300mg/kg treatment groups, respectively.
Poly (I: C) and SARS-CoV-2 spinous process protein establish mouse virus infectivity ARDS model 6 hours later, use 4% pentobarbital to kill the mouse, and use forceps and scissors to separate and obtain the lung tissue of the mouse, and place in 4% paraformaldehyde for fixation. Embedding the obtained lung tissue, taking a section of about 5mm by using a tissue microtome, and putting the tissue section in xylene for dewaxing for 5-10 min; gradually dehydrating with ethanol: changing fresh dimethylbenzene, and dewaxing for 5-10 min; soaking in anhydrous ethanol for 5min, 90% ethanol for 2min, 70% ethanol for 2min, and distilled water for 2min for dehydration. Staining with hematoxylin for 5min, and washing with tap water; differentiating with hydrochloric acid and ethanol for 30s, soaking in tap water for 15min, and placing in Yihong liquid for 2-3 min; then carrying out conventional dehydration, transparency and mounting treatment: dehydrating with fresh 95% ethanol (I) for 2s, dehydrating with 95% ethanol (II) for 2min, and treating with xylene for 5 min. Dehydrating, transparent and sealing: dehydrating with 95% ethanol for 2s, soaking with 100% ethanol (I) for 30s, and soaking with 100% ethanol (II) for 1 min. Fresh xylene was replaced and the solution was then cleared for 5 min. Encapsulated with a neutral gum or other encapsulating agent. And (4) observing under a microscope.
The results show that: the nucleus was blue and the cytoplasm was pink or red (see fig. 3). In FIG. 3, A shows: compared with a control group, the pulmonary alveolar space broadening degree of the experimental group treated by 100mg/kg is reduced, the interstitial congestion edema is reduced, the pulmonary alveolar space is broadened, and the small airway injury is weakened; in FIG. 3, B shows: compared with the control group, the experimental group treated by 300mg/kg has reduced alveolar septal broadening, interstitial hyperemia and edema, widened alveolar space and weakened small airway injury. The results show that: the acetylshikonin can remarkably inhibit lung injury caused by acute respiratory distress syndrome of mice induced by Poly (I: C) and SARS-CoV-2 spinous process protein, and can be used for preparing anti-lung inflammatory factor storm medicine for preventing and treating pneumonia.
Claims (6)
1. Application of acetylshikonin in preparing medicine for resisting lung inflammation factor storm is provided.
2. Use according to claim 1, wherein the acetylshikonin is used in the manufacture of a medicament for the treatment of viral pneumonia, bacterial pneumonia and mycoplasmal pneumonia.
3. The use of claim 1, wherein the acetylshikonin is capable of inhibiting the inflammatory factor storm response in the mouse lung caused by polyinosinic acid and SARS-CoV-2 spike protein.
4. The use of claim 1, wherein the acetylshikonin is capable of alleviating acute lung injury caused by polyinosinic acid and SARS-CoV-2 spinous process protein in mouse lung tissue.
5. The use as claimed in claim 1, wherein the acetylshikonin is used in an amount of 2.5-10 μ M in vitro and in an amount of 100-300mg/kg in vivo.
6. The use as claimed in claim 5, wherein the administration of acetylshikonin is oral, gavage, intraperitoneal or aerosol inhalation.
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