CN109432130A - Application of the mescenchymal stem cell excretion body in the drug that preparation prevents and treats induced lung injury - Google Patents
Application of the mescenchymal stem cell excretion body in the drug that preparation prevents and treats induced lung injury Download PDFInfo
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- CN109432130A CN109432130A CN201811564675.3A CN201811564675A CN109432130A CN 109432130 A CN109432130 A CN 109432130A CN 201811564675 A CN201811564675 A CN 201811564675A CN 109432130 A CN109432130 A CN 109432130A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
The invention discloses application of the mescenchymal stem cell excretion body in the drug that preparation prevents and treats induced lung injury, using mescenchymal stem cell excretion body tail vein injection drug treatment through postradiation injury of lungs mouse, inflammatory factor level (IL-1 β is effectively reduced, IL-6, TNF-α, TGF-β), effectively improve mouse survival rate, pneumonia and pulmonary fibrosis lesion caused by reducing because of induced lung injury, mescenchymal stem cell excretion body is with high security, chemical property is stablized, it is easy to store, a kind of new way provided for safe and effective therapeutic radiation injury of lungs.
Description
Technical field
The present invention relates to stem cell applied technical field, in particular to a kind of mescenchymal stem cell excretion body prevents in preparation
With the application in the drug of therapeutic radiation injury of lungs.
Background technique
Radiation treatment (Radiotherapy, radiotherapy), which is that one kind is widely applied during treating malignant tumor, to be controlled
Treatment mode, to thoracic malignant tumors such as lung cancer, breast cancer, the cancer of the esophagus, mediastinum malignant tumour significant effect.Lead to when radiation treatment
Induced lung injury (radiation-induced lung injury, RILI) often occurs.RILI is serious in Patients During Radiotherapy
Complication is mainly shown as that radiation pneumonitis, stethemia, pulmonary edema increase or hyaline membrane is formed, eventually forms
Pulmonary interstitial fibrosis.
Currently, clinically lacking to the effective treatment method of induced lung injury, common treatment mode is oxygen uptake, cough-relieving, puts down
Asthma etc., can only adjust serious patient RILI or stop radiotherapy；Therefore, induced lung injury harm becomes restriction radioactivity and controls
The bottleneck of application is treated, mescenchymal stem cell treatment achieves certain therapeutic effect in mouse level to induced lung injury, but
Since there are many drawbacks for mescenchymal stem cell, such as self mescenchymal stem cell materials, cultivation cycle are long, and allosome mesenchyma is dry thin
There is certain immune risk and ethics problem in born of the same parents, constrain its clinical application；Since mescenchymal stem cell excretion body does not contain
Inhereditary material has evaded a series of problems, becomes the potential treatment means of therapeutic radiation injury of lungs.
Summary of the invention
For above situation, for the defect for overcoming the prior art, the object of the present invention is to provide mescenchymal stem cell excretions
Application of the body in the drug that preparation prevents and treats induced lung injury can overcome and restrict because induced lung injury harm becomes
Inflammatory factor level is effectively reduced in the bottleneck of radiation treatment application, and pneumonia caused by reducing because of induced lung injury and lung are fine
Dimensionization lesion improves mouse survival rate, and mescenchymal stem cell excretion body is with high security, chemical property is stable, is easy to store,
A kind of new way provided for safe and effective therapeutic radiation injury of lungs.
To achieve the above object, the application provides a kind of mescenchymal stem cell excretion body and prevents and treats radioactivity in preparation
Application in the drug of injury of lungs.
Further, being administered for the mescenchymal stem cell excretion body is inputted in the front/rear vein of induced lung injury,
Inflammatory factor level in blood is reduced, pneumonia and pulmonary fibrosis degree are delayed.
Further, the inflammatory factor includes IL-1 β, IL-6, TNF-α, TGF-β.
Further, the mescenchymal stem cell excretion body derives from mescenchymal stem cell, and the mescenchymal stem cell comes
Derived from marrow.
Further, the mescenchymal stem cell is prepared by the following method to obtain: taking mouse thigh to be placed in and contains
Have in 2/1000ths dual anti-PBS solution, later, the both ends of bone are cut off in super-clean bench, is gone out marrow with culture medium
Come, is placed in culture dish；The culture medium is removed after being cultivated in 37 DEG C of cell incubators 2 hours, 2 hours, is replaced fresh
The culture medium, be placed in 37 DEG C of cultures；Later, the primary culture medium was changed every 2 days, when cell quantity reach 80% with
On, it is passed on.
Further, the culture medium is the DMEM in high glucose culture medium containing 10% serum.
Further, the mescenchymal stem cell excretion body, is prepared by the following method to obtain: selecting mesenchyma dry
Cell is cultivated, and when cell density reaches 90%, discards former culture medium, is put after changing α-MEM serum free medium culture 12h
Enter hypoxemia incubator culture, collects supernatant after 48h；By the supernatant in 4 DEG C, 3000rpm is centrifuged 10min, then removes
Cell fragment, by the supernatant after removal cell fragment in 4 DEG C, 104G is centrifuged 1h, discards supernatant, and PBS solution is added and is resuspended；Again
Ultracentrifugation 1h, discards supernatant, and 100 μ l PBS solutions are added and are resuspended, -80 DEG C save backup.
Further, the condition of the hypoxemia incubator is set as 37 DEG C, 94%N2, 1%O2, 5%CO2。
Further, the mescenchymal stem cell excretion body is extracted using density-gradient centrifugation method.
Further, the mescenchymal stem cell excretion body passes through intravenous administration.
The present invention provides a kind of mescenchymal stem cell excretion body in the drug that preparation prevents and treats induced lung injury
Application, by after radiation injury of lungs mouse tail vein injection extract mesenchymal stem cell excretion body, using horse
Loose trichrome stain mode is dyed front/rear lung fibroblast is radiated, observation excretion body to pneumonia caused by injury of lungs and
The therapeutic effect of pulmonary fibrosis, research find that inflammatory factor level is effectively reduced in mesenchymal stem cell excretion physical efficiency, effectively
Mouse survival rate is improved, is reduced because of pneumonia and pulmonary fibrosis lesion caused by induced lung injury, outside mesenchymal stem cell
Secrete body with high security, chemical property is stable, is easy to store, the one kind provided for safe and effective therapeutic radiation injury of lungs is new
Approach.
Detailed description of the invention
Fig. 1 is that mesenchymal stem cell provided in an embodiment of the present invention identifies table；
Fig. 2 is extraction excretion body western blotting qualification result figure provided in an embodiment of the present invention；
Fig. 3 is 3 Zhou Houwei irradiation group of radioactivity provided in an embodiment of the present invention, radioactivity processing group, excretion body treatment group
As a result comparative diagram is compared；
Fig. 4 is that radioactivity provided in an embodiment of the present invention handles non-irradiation group after March, irradiation group, treatment group's result are compared
Comparative diagram；
Fig. 5 is blood TGF β testing result comparison diagram after radioactivity provided in an embodiment of the present invention is handled 3 weeks；
Fig. 6 is blood IL1- β testing result comparison diagram after radioactivity provided in an embodiment of the present invention is handled 3 weeks；
Fig. 7 is blood TNF-α testing result comparison diagram after radioactivity provided in an embodiment of the present invention is handled 3 weeks；
Fig. 8 is blood IL-6 testing result comparison diagram after radioactivity provided in an embodiment of the present invention is handled 3 weeks；
Fig. 9 is survival rate curve after radioactivity provided in an embodiment of the present invention processing.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
The present invention provides a kind of mescenchymal stem cell excretion bodies to prepare the drug for preventing and treating induced lung injury
In application.
Embodiment:
One, next day after radio exposure is taken to be injected intravenously 100mg excretion body, later Testing index.
The foundation of induced lung injury mouse model: 8-10 week old C57BL/6 mouse is chosen, linear accelerator 4- is used
6MV irradiates the entire thoracic cavity of every mouse, and head, abdomen and four limbs are shielded with leads.
Two, the separation of mouse bone marrow cells mesenchyma, culture, identification
The mouse irradiated 6-8 weeks is chosen, the alcohol disinfecting later with 75% is anaesthetized.Mouse thigh is taken to be placed in containing thousand points
Two dual anti-(ampicillin, kanamycins) PBS solution in, as far as possible removal bone on its hetero-organization.Later, ultra-clean
The both ends that bone is cut off in platform, with the DMEM in high glucose culture for containing 10% serum, 1 ‰ dual anti-(ampicillin, kanamycins)
Base rushes out marrow, is placed in culture dish, removes culture medium after cultivating in 37 DEG C of cell incubators 2 hours, 2 hours,
Renew fresh culture medium, is placed in 37 DEG C of cultures；Later, every 2 days one subcultures of replacement, when cell quantity reach 80% with
On, carry out secondary culture；After secondary culture to the third generation, the identification of cell type, mark used are carried out using streaming technology
Note object is CD90.2+, CD44+, CD73+, CD105+, CD45-, CD34-, and testing result is shown in Fig. 1, in mouse mesenchymal cell
It is 95.32%, CD73+ expression rate is 98.2%, CD105+ expression rate that CD90.2+ expression rate, which is 97.00%, CD44+ expression rate,
Be 2.54%, CD34- expression rate for 96.00%, CD45- expression rate it is 2.05%, shows mouse by radioactive damage.
Three, the separation of MSCs (mescenchymal stem cell) excretion body and identification
A) MSCs excretion body separates
MSCs is selected to cultivate to the third generation, (about 10 when cell density reaches 90%7A cell), discard former high sugar
DMEM culture medium is put into hypoxemia incubator (37 DEG C, 94%N after changing α-MEM serum free medium culture 12h2, 1%O2, 5%
CO2) under the conditions of, after cultivating 48h, collect supernatant.By the supernatant being collected into 4 DEG C, 3000rpm is centrifuged 10min, and removal is thin
Obtained supernatant is moved to ultracentrifugation pipe by born of the same parents' fragment, and 4 DEG C, 104G ultracentrifugation 1h, discards supernatant, PBS is added into precipitating
It is resuspended；Ultracentrifugation 1h again is discarded supernatant, and 100 μ l PBS are added and are resuspended, -80 DEG C save backup.
B) MSCs excretion body western blotting qualification
(1) protease inhibitors PMSF (phenylmethylsulfonyl fluoride) is added after RIPA lysate melts.
(2) -80 DEG C of excretion bodies frozen are taken out, it then will be appropriate in 20 μ l RIPA lysates/1mg excretion body ratio
RIPA lysate is added in 1.5ml centrifuge tube, is sufficiently homogenized, places 30min on ice, obtain cleavage mixture.
(3) cleavage mixture is put into refrigerated centrifuge, 4 DEG C, 1200rpm is centrifuged 10min, Aspirate supernatant.
(4) a small amount of supernatant is taken, is further diluted with RIPA lysate, measures total egg with BCA method (protein concentration detection)
White concentration.Adjusting sample room difference by concentration RIPA lysate keeps concentration consistent.
(5) be added 1/5 volume 6xloading buffer (Tris-HCl (pH=6.8) 312.5mM, 10%SDS,
50% glycerol, 2% beta -mercaptoethanol, 0.05% bromophenol blue), boiling water bath boils 5min after mixing, is denaturalized albumen sufficiently.
(6) -80 DEG C or direct electrophoresis are deposited in after sample is cooled to room temperature.
(7) polyacrylamide gel is prepared, the 4 μ l of loading after being gelled carries out SDS-PAGE electrophoresis.Every piece of glue is permanent by 20mA
Flow electrophoresis.
(8) transferring film operation, the wet robin of 300mA constant current are carried out after electrophoresis, albumen is gone to NC film (nitre by transferring film 1-2h
Acid cellulose film) or pvdf membrane (PVDF membrane) on.
(9) after removing film, with the TBST containing 5% skimmed milk power, room temperature is closed one hour on shaking table.
(10) film is incubated in containing 1%BSA (bovine serum albumin(BSA)) and 0.05% sodium azide after washing film with TBST
In TBST primary antibody, 4 DEG C of shaking tables shaken over night at a slow speed.
(11) it is washed four times with TBST, each 15min.
(12) secondary antibody (containing 5% skimmed milk power, HRP (horseradish peroxidase) marks the TBST of secondary antibody) is added, room temperature exists
Low speed is incubated for one hour on shaking table.
(13) it is washed four times with TBST, each 15min.Darkroom exposure development after addition developing solution AB liquid.Experimental result is used
ImageJ software quantitative analysis.
As shown in Fig. 2, having band in the corresponding position excretion body characteristics PROTEIN C D9, CD63 and CD81, illustrate isolated
Product be MSCs excretion body.
Four, inflammatory factor detects, and is directly detected according to correlation factor ELISA detection kit specification method.
In a specific embodiment, before induced lung injury 1 week by the way of tail vein injection excretion body into
Row administration mode, plays preventive effect, mainly takes mouse being fixed on limitation activity on bracket, finds rat-tail with insulin needle
Excretion body is administered by vein by caudal vein.Excretion body can be by venous return to heart subsequently into pulmonary circulation, will
Drug takes in lungs, can also be sprayed and is administered by tracheae, by mouse anesthesia (5% chloraldurate, 20 μ l), find gas
26G vein is detained needle hose and is sent into mouse tracheae by tube opening, is connect syringe and is sent into excretion body intratracheally, excretion body can lead to
Tracheae is crossed to enter in lung tissue；It is preferred that administration single dose 100mg excretion body/100 μ l physiological saline.
In a specific embodiment, after induced lung injury 1 week by the way of tail vein injection excretion body into
Row administration；Radiation sexual stimulus is carried out first, it is preferable that whole using linear accelerator 4-6MV every mouse of energy exposure
A thoracic cavity, head, abdomen and four limbs are shielded with leads；The treatment of excretion body is carried out after 1 week.It mainly takes and mouse is fixed on bracket
Upper limitation activity finds caudal vein with insulin needle and is administered excretion body by caudal vein, and excretion body can be by quiet
Arteries and veins flows back into heart subsequently into pulmonary circulation, and drug is taken in lungs；It can also be sprayed and be administered by tracheae, by mouse
It anaesthetizes (5% chloraldurate, 20 μ l), finds tracheostomy, 26G vein is detained needle hose and is sent into mouse tracheae, connects syringe
Excretion body is sent into intratracheally, excretion body can be entered in lung tissue by tracheae；Such as Fig. 4, preferably administration will be between after extraction
Mesenchymal stem cells source excretion body single dose 100mg excretion body/100 μ l physiological saline, ejection preparation arrive body by intravenous injection
It is interior, by venous return to heart subsequently into pulmonary circulation, take drug the organs such as to liver and lung, reduce in blood inflammation because
Horizontal IL-1 β of son, IL-6, TNF-α, TGF-β, delay pneumonia and pulmonary fibrosis degree；After showing radioactivity 3 weeks such as Fig. 3, phase
Than control (stereotype blocks non-irradiation group, left figure), radioactivity processing group (middle) H&E dyeing is with obvious lesion group outside alveolar
It knits, shows that pneumonia exists, radioactivity model success, excretion body treatment group (right figure) pathological tissues reduce, and pneumonia is alleviated；Specifically
Ground, such as Fig. 5, blood TGF β testing result after radioactivity is handled 3 weeks, compared to sexual stimulus group is not radiated, simple radioactivity is handled
Group blood TGF β improves 1.6 times, and simple excretion body processing TGF-β is with control group without significant difference, model excretion body treatment group phase
Than in model group, TGF-β reduces by 23% or so；Such as Fig. 6, blood IL1- β testing result after radioactivity is handled 3 weeks, compared to not
Sexual stimulus group is radiated, simple radioactivity processing group blood IL1- β improves 3.55 times, and simple excretion body processing IL1- β is with control group
Without significant difference, model excretion body treatment group reduces by 60% or so compared to model group, IL1- β；Such as Fig. 7, radioactivity is handled 3 weeks
Blood TNF-α testing result afterwards, compared to sexual stimulus group is not radiated, simple radioactivity processing group blood TNF-α improves 3 times, list
With control group without significant difference, model excretion body treatment group reduces pure excretion body processing TNF-α compared to model group, TNF-α
26% or so；Such as Fig. 8, blood IL-6 testing result after radioactivity is handled 3 weeks is radiated merely compared to sexual stimulus group is not radiated
Property processing group blood IL-6 improve 2.4 times, simple excretion body processing IL-6 is with control group without significant difference, the treatment of model excretion body
Group reduces by 50% or so compared to model group, IL-6；Fig. 9, it can be seen that compared to control (stereotype blocks non-irradiation group, PBS), put
Penetrating property processing group (radiation sexual stimulus+PBS group) mouse is all dead at 57 weeks, excretion body treatment group (radiation sexual stimulus+excretion
Body) survival rate improved.
In a kind of preferred embodiment, source for mesenchymal stem cells excretion body derives from mescenchymal stem cell, and mesenchyma is dry thin
Born of the same parents derive from marrow, can also be from fat mesenchymal stem cell, umbilical cord blood mesenchymal stem cells, umbilical cord mesenchymal stem cells, placenta
It is extracted in mescenchymal stem cell, with high security, is easy to store and adopts, acquire conveniently.
In a specific embodiment, mesenchymal stem cell excretion body be by third and fourth, five generation mesenchymas it is dry thin
Intracrine culture, the cell concentration that the first and second generation mescenchymal stem cell generates is seldom, and standard is not achieved, and the speed of growth is relatively more slow
Slowly, therefore selection cell concentration is sufficient, and fast third and fourth of the speed of growth, five generation mescenchymal stem cells carry out secretion culture.
In a specific embodiment, it extracts mescenchymal stem cell excretion body and uses density-gradient centrifugation method, the method
Good separating effect can once obtain purer particle, wide adaptation range.
The foregoing is merely a prefered embodiment of the invention, is not intended to limit the invention, all in the spirit and principles in the present invention
Within, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (10)
1. application of the mescenchymal stem cell excretion body in the drug that preparation prevents and treats induced lung injury.
2. the drug that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
In application, which is characterized in that the front/rear vein of induced lung injury input the mescenchymal stem cell excretion body carry out to
Medicine reduces inflammatory factor level in blood, delays pneumonia and pulmonary fibrosis degree.
3. the drug that mescenchymal stem cell excretion body according to claim 2 prevents and treats induced lung injury in preparation
In application, which is characterized in that the inflammatory factor includes IL-1 β, IL-6, TNF-α, TGF-β.
4. the drug that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
In application, which is characterized in that the mescenchymal stem cell excretion body derive from mescenchymal stem cell, the mescenchymal stem cell
From marrow.
5. the drug that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
In application, which is characterized in that mescenchymal stem cell is prepared by the following method to obtain: take mouse thigh be placed in containing
In 2/1000ths dual anti-PBS solution, later, the both ends of bone are cut off in super-clean bench, rushed out marrow with culture medium,
It is placed in culture dish；The culture medium is removed after being cultivated in 37 DEG C of cell incubators 2 hours, 2 hours, replaces fresh institute
Culture medium is stated, 37 DEG C of cultures are placed in；Later, the primary culture medium was changed every 2 days, when cell quantity reaches 80% or more, into
Row secondary culture.
6. the drug that mescenchymal stem cell excretion body according to claim 5 prevents and treats induced lung injury in preparation
In application, which is characterized in that the culture medium be the DMEM in high glucose culture medium containing 10% serum.
7. the drug that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
In application, which is characterized in that the mescenchymal stem cell excretion body is prepared by the following method to obtain: fill between selection
Matter stem cell is cultivated, and when cell density reaches 90%, discards former culture medium, changes α-MEM serum free medium culture 12h
After be put into hypoxemia incubator culture, collect supernatant after 48h；By the supernatant in 4 DEG C, 3000rpm is centrifuged 10min, then
Cell fragment is removed, by the supernatant after removal cell fragment in 4 DEG C, 104G is centrifuged 1h, discards supernatant, and PBS solution weight is added
It is outstanding；Ultracentrifugation 1h again is discarded supernatant, and 100 μ lPBS solution are added and are resuspended, -80 DEG C save backup.
8. the drug that mescenchymal stem cell excretion body according to claim 7 prevents and treats induced lung injury in preparation
In application, which is characterized in that the condition of the hypoxemia incubator is set as 37 DEG C, 94%N2, 1%O2, 5%CO2。
9. the drug that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
In application, which is characterized in that take the mescenchymal stem cell excretion body using density-gradient centrifugation method.
10. the medicine that mescenchymal stem cell excretion body according to claim 1 prevents and treats induced lung injury in preparation
Application in object, which is characterized in that the mescenchymal stem cell excretion body passes through intravenous administration.
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