CN1772001A - Application of viscid serratia vaccine in preparing medicine for treating bronchial asthma - Google Patents
Application of viscid serratia vaccine in preparing medicine for treating bronchial asthma Download PDFInfo
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Abstract
The present invention discloses the application of viscid serratia vaccine in preparing medicine for treating bronchial asthma. Animal experiment shows that viscid serratia vaccine has obvious effect of treating bronchial asthma, and it is found via research on several kinds of asthma animal models that viscid serratia vaccine can inhibit the allurgen casued acidophilic granulocyte increase in asthma animal respiratory tract, reduce bronchia reactivity, inhibit lung and systemic Th2 type immunological response, and reduce allurgen induced IL-4 level and IgE synthesis. What is more important is that viscid serratia vaccine has inapproachable safety compared with BCG. Therefore, viscid serratia vaccine has application foreground in preventing and treating asthma.
Description
Technical field
The present invention relates to the purposes of Becterin of Serratia marcescens, relate in particular to the purposes of Becterin of Serratia marcescens in pharmaceutical field.
Background technology
The bacteria characteristic of serratia marcesens vaccine and relevant data in the file of CN02111996.1 patent disclosure, have had detailed description.
This vaccine is a gram negative bacilli, and whole body flagellum is dynamic, there are not folder film and brood cell, this bacterium is under general aerobic condition, and well-grown on 37 ℃ of ordinary culture mediums is on the plain agar flat board, bacterium colony is smooth moistening, projection, neat in edge, rounded, biochemical reaction: energy glucose fermentation, sucrose, mannitol, amygdalin, produce not aerogenesis of acid.Azymic rhamnose, arabinose, close disaccharide.Can produce the outer deoxyribonuclease of born of the same parents.Bacterium numbering: CGMCCNo.0744, classification name: serratia marcescens Serratia marcescens.
CN02111996.1 also discloses the drug effect of serratia marcescens.It has antitumor action, and the main mechanism of action is the effect of direct killing tumor cell, still keeps medium direct cytotoxicity after the deactivation.Vaccine or its crude extract (cell membranous structure and ribosome thereof etc.) can be made the antineoplastic immunomodulator.Comprise with the medicine of serratia marcescens preparation or the therapeutic domain of immune formulation: heating and skin erythema and behcet's syndrome or the like of tumor, cancerous ascites pleural fluid, immunomodulating, auxiliary chemicotherapy, leukocyte increasing, psoriasis, condyloma acuminatum, lupus erythematosus.
Asthma is a kind of common respiratory system chronic tracheitis disease property disease.Pathogeny and Th1/Th2 cytokines proportional imbalance are closely related, show as mainly that the Th2 cell number increases, hyperfunctioning.Th2 cytokines that secretion increases such as interleukin (IL-3), IL-4, IL-5, IL-13 etc. can induce IgE to produce, stimulate eosinophilic granulocyte's propagation, activation and then cause respiratory inflammation, bronchospasm by secreting multiple pro-inflammatory mediator.At present, glucocorticoid (GCS) is the most effective medicine of treatment asthma, the target of its treatment mainly concentrates on the chronic inflammatory disease of trachea, and it can not fundamentally change the generating process of disease, can not induce helper T lymphocyte 2 (Th2) to transform to helper T lymphocyte 1 (Th1).
New studies show that at present, Th1 cytokines such as IL-12, IFN-(IFN-γ) etc. participate in the adjusting of Th cell differentiation, can suppress the generation of Th2 cytokines IL-4 and IL-5, and block the synthetic of IgE, thus effective former inductive trachea high response of inhibitory reaction.Thereby the emphasis to treating asthma is turned to immunization therapy, especially how to be promoted the Th0 cell to the generation control asthma allergy of Th1 cell differentiation, inhibition Th2 cytokines the focus that more becomes common concern to take place, develops by simple preventing respiratory spasm at present.Although the various countries scientist is devoted to study the direct antagonist of using Th1 cytokine or Th2 cytokines in the hope of being used for the asthma control for many years, all too single because of effect, effect is not fully up to expectations.Obviously,, for the disease of multiple inflammatory mediator and the morbidity of cytokine fellowship, block a certain cytokine and be difficult to whole network is caused too big influence for a kind of like this.Seeking a kind of strong immune regulator that can improve whole Th1/Th2 imbalance state becomes the hope place of asthma control.
The object of the present invention is to provide the new purposes of Becterin of Serratia marcescens, promptly the new purposes in pharmacy specifically provides its application in preparation treatment asthmatic medicament.
When Becterin of Serratia marcescens is used for preparation treatment bronchial asthma medicine, can adopts conventional method that the serratia marcescens bacterium is cultivated, and from culture, collect Becterin of Serratia marcescens by the method for routine.Conventional cultural method is as follows: adopt the solid culture production labor to make seed.After the inoculation production labor was made seed in nutrient agar, 1-2 inoculation of going down to posterity continuously was inoculated in Ke Shi bottle nutrient agar inclined-plane at last, through 35-37 ℃ of aerobic cultivation 18-20 hour, is no more than for 4 generations.By the bottle microscopy, the person is discarded the living contaminants before gathering.The lawn of gathering places the abundant mixing of the injection normal saline of sterilization, and four layers of silk filter.By Chinese bacterial turbidity standard test, become 400～60,000,000,000 bacterium/ml by standard opacity tube concentration dilution, the thalline adding of collection is no more than the sterilization of 0.5% (ml/ml) formalin and carries out sterility test after 48 hours, and any bacteria growing must not be arranged.During cultivation, to condition of culture, there is no requirement very, be as the criterion with the growth of suitable Becterin of Serratia marcescens, its pH scope is 2～9, and temperature is 4～40 ℃.
The culture that adopts said method to obtain by suitable for separation, can obtain Becterin of Serratia marcescens.Said suitable for separation is washed with normal saline after scraping bacterium from Nutrient agar, and 12000 commentaries on classics/per minutes are centrifugal, collects antibacterial in normal saline.
The inventor finds, serratia marcesens Seedling Salmonella has the obvious treatment effect to bronchial asthma, animal experiment proves, even Becterin of Serratia marcescens of the present invention is when a large amount of the use, the behavior of animal is also without any unusually, the safety research of acute toxicity, chronic toxicity proof Becterin of Serratia marcescens does not have toxicity, by national new drug reviewing, is obtaining new biological product I kind new medicine certificate aspect the pernicious ascites pleural fluid of treatment in 2000.
Can put on the patient who needs treatment with Becterin of Serratia marcescens and pharmaceutically acceptable carrier with the form of compositions, general dosage is 0.016mg/ kg body weight every day, specifically can change according to patient's age, the state of an illness etc.
Said carrier is meant the pharmaceutical carrier of pharmaceutical field routine, and as diluent water etc., the compositions that Becterin of Serratia marcescens and above-mentioned carrier constitute can put on the patient who needs this treatment by intravenous injection or hypodermic form.
In the preparation, the weight content of Becterin of Serratia marcescens is 0.1～99.9%, and preferred content is 0.5～90%.
Bacillus calmette-guerin vaccine is a kind of live bacterial vaccines of attenuation, and purpose is to be used for preventing generation lungy.But because it belongs to the live bacterial vaccines of attenuation, exist virulence and reply the possibility that changes, have certain risk.The toxic and side effects of relevant bacillus calmette-guerin vaccine visible a lot of report (document: Fan Yongzhen, Shi Yulin, Liang Yanmei.Side reaction of bacillus calmette-guerin vaccine immunity inoculation and treatment principle, Inner Mongol preventive medicine 1999; 24 (3): 131-133).The local ulcer that has disseminated tuberculosis to infect, do not heal for a long time, ulcer surface is big, by inoculation side and the thymus, the upper and lower lymph node diabrosis of clavicle, the equal diabrosis of the lymph nodes of body as a whole that continues, the ulcer surface exudate has a large amount of tulases growths.Local cold abscess, purulent lymphadenitis etc.These toxic and side effects are relevant with some bacterial strain of bacillus calmette-guerin vaccine, lot number mostly.Animal experiment proves that Becterin of Serratia marcescens has the obvious treatment effect to bronchial asthma, the more important thing is that the serratia marcesens Seedling compares with BCG, because it is the vaccine of deactivation, has unrivaled safety.Thereby Becterin of Serratia marcescens has the prospect of the prevention and the treatment of asthma.
In order to understand essence of the present invention better, below will its new purposes in pharmaceutical field be described with the pharmacological testing and the result thereof of Becterin of Serratia marcescens.
The specific embodiment
Embodiment 1
The cultivation of Becterin of Serratia marcescens and collection:
Adopt the solid culture production labor to make seed.After the inoculation production labor was made seed in nutrient agar, continuous 2 inoculations of going down to posterity were inoculated in Ke Shi bottle nutrient agar inclined-plane at last, through 37 ℃ of aerobic cultivations 19 hours, are no more than for 4 generations.During cultivation, to condition of culture, there is no requirement very, be as the criterion with the growth of suitable Becterin of Serratia marcescens, its pH scope is 2～9, and temperature is 4～40 ℃.This experiment pH is 7, and temperature is 37 ℃.By the bottle microscopy, the person is discarded the living contaminants before gathering.The lawn of gathering places the abundant mixing of the injection normal saline of sterilization, and four layers of silk filter.By Chinese bacterial turbidity standard test, become 45,000,000,000 bacterium/ml by standard opacity tube concentration dilution, the thalline adding of collection is no more than the sterilization of 0.5% (ml/ml) formalin and carries out sterility test after 48 hours, and any bacteria growing must not be arranged.
Getting 1000ml does not have the deionized pure distilled water of thermal source with the dissolving of 32mg Becterin of Serratia marcescens, mix homogeneously, and sterilization is configured to the injection of 0.32g/ml, and finished product is made in bottling.
Embodiment 2
Getting 1000ml does not have the deionized pure distilled water of thermal source with the dissolving of 640mg Becterin of Serratia marcescens, mix homogeneously, and sterilization is configured to the injection of 0.64mg/ml, and finished product is made in bottling.
Embodiment 3
Concrete experiment and division is as follows as a result:
One, animal grouping and modelling
40 of male Wistar rats (The 2nd Army Medical College Experimental Animal Center), 2～3 monthly ages, body weight (200 ± 50) g.Be divided into four groups at random, 10 every group.Normal control group (A group): replace serratia marcescens Seedling, sensitinogen injection and atomizing to suck with phosphate buffer (PBS); Serratia marcescens Seedling immune group (B group): the serratia marcescens Seedling 0.32mg of every rat intradermal injection embodiment 2 replaces sensitinogen injection and atomizing suction with PBS liquid after 8 weeks; A, B organize after 11 weeks and take same procedure to handle with C, D group; Asthmatic model group (C group): for the serratia marcescens Seedling is injected the back asthmatic model group of setting up, injected the serratia marcescens Seedling, sets up asthmatic model by the D group of methods again after 8 weeks by the B group of methods; Conventional asthmatic model group (D group): the asthmatic model of do not use the immunity of serratia marcescens Seedling, making according to a conventional method.
The animal model in asthma preparation
Adopt egg protein sensitization and excite and set up asthma mouse model.A subcutaneous injection 10mg chicken egg white (OVA, U.S. Sigma company) and 200mg aluminium hydroxide (being mixed in the PBS liquid of 1ml) next day of every rat.After OVA sensitization, began to excite in the 15th day, rat is placed a hermetic container, gives 2%OVA phosphate buffer (OVAPBS) 50ml atomizing and suck and stimulate, every day 1 time, each 20min, continuous 7 days.
Document: Yu Yanliang. Sun Xiuming, Li Cuili, etc. bacillus calmette-guerin vaccine is breathed the critical illness monitoring magazine to the influence China of asthmatic guinea pigs, and 2002; 1:154～156; And document: Huang Jingyue, Yu Riyue, Zhu Jiagu is etc. cold sense peace diaphoresis relieving cough and asthma pharmacology effect experimentation. Chinese experimental pharmacology of Chinese medical formulae magazine, to this have detailed report at 1998,7 (2): 31;
A subcutaneous injection 10mg chicken egg white (OVA, U.S. Sigma company) and 200mg aluminium hydroxide (being mixed in the PBS liquid of 1ml) next day of every rat.After OVA sensitization, began to excite in the 15th day, rat is placed a hermetic container, gives 2%OVA phosphate buffer (OVAPBS) 50ml atomizing and suck and stimulate, every day 1 time, each 20min, continuous 7 days.
The result:
Observe to find that the D group after atomizing sucks OVAPBS liquid, begins to occur significantly women's head-ornaments portion pruritus about 5～7min, and then accelerated breathing deepens, quiet few moving, back of a bow, forelimb contract and lift, nod breathings, weight person's audible wheezing sound, the asthma sample occurred and have showed.As seen leave over more dung urine after taking out animal.A, B, all not above-mentioned performance of C group (accidental head, facial pruritus), and keep normality from start to finish.
Two. the evaluation of asthmatic model
The success or not of asthmatic model, definite: (1) provocative reaction according to following several respects; (2) bronchoalveolar lavage fluid (BALF) is done cell smear and conventional H E dyeing; (3) the broncho-pulmonary tissue slice is done conventional H E dyeing; (4) trachea is reactive measures: with tracheal pressure rise 50% o'clock methacholine concentration (PC50) be index, adjusting animal respirator (Zhejiang Medical university zoopery instrument plant), frequency is that 100 times/min, tidal volume are 0.18ml.In exciting back 24h for last 1 time with 20% urethane by 7ml/kg intraperitoneal administration anesthetized rat after the incision of circulation of qi promoting pipe, insert suitable spile, methacholine liquid (concentration range 0.20～3.20g/L that suction PBS liquid and the concentration of successively atomizing in order increases progressively, with the preparation of PBS liquid), each concentration atomizing sucks 3min, interval 5min, before atomizing sucks, after connect animal respirator and measure tracheal pressure, with the tracheal pressure behind the atomizing suction PBS liquid is that radix calculates the pressure that pressure raise at 50% o'clock, and required atomizing sucks methacholine concentration as PC50 when reaching this pressure.
The result:
Each is organized, and cytology's change sees the following form in the BALF of Rats.
Table 1 bronchoalveolar lavage fluid cell and detection (x ± s)
| Group | n | Total cellular score | Lymphocyte | Eosinophilic granulocyte | Mastocyte |
| The A group | 10 | 82.56±24 | 49.06±9.13 | 0.67±0.14 | 0.83±0.23 |
| The B group | 10 | 1067.00±135.16 ** | 577.20±79.13 ** | 41.5±12.9 ** | 31.68±7 ** |
| The C group | 10 | 566.87±105 ** | 352.00±88.7 ** | 18.98±7.8 ** | 13.16±5 ** |
| The D group | 10 | 236.87±75 | 138.00±44.3 | 38.64±13 | 27.16±8.2 |
B, C group and D group compare,
*P＜0.01 (statistics is analyzed with the SPSS statistical software)
EOS (eosinophilic granulocyte) is obviously more than the A group in BALF for the D group, and prompting D group exists the trachea allergic inflammation to change; The lymphocyte number of B, C, D group is obviously more than the A group, BALF medium-sized lymphocyte showed increased after B and C group, the immunity of explanation serratia marcescens Seedling especially, and the bronchovesicular medium-sized lymphocyte may be subjected to obvious activation; (0.26 ± 0.13g/L) then is starkly lower than A, B, C group (is respectively 3.12 ± 0.93,3.25 ± 0.78,2.98 ± 0.98g/L) and the PC50 comparing difference does not have significance between A, B, C group, prompting D group exists the trachea reactivity to increase to D group PC50; But the EOS (eosinophilic granulocyte) of C group and PC50 and A, B group comparing difference do not have significance, and C organizes does not all have asthma on pathology and pathophysiology evidence is described, promptly the asthmatic model of C group is false.Result of study shows, the asthmatic model that confirms the D group from subjective sign, pathology or pathophysiology multi-angle is successful, fail to set up successful asthmatic model and use in C group with quadrat method, illustrate inject the serratia marcescens Seedling in advance after, can prevent the generation of rat sensitization asthma.
Three, the collection of BALF medium-sized lymphocyte and processing
Circulation of qi promoting cannula in rat blood sampling back with PBS liquid lavation bronchovesicular and collect BALF, injects 8ml at every turn, wash 2 times repeatedly after sucking-off, totally 3 times, the response rate reaches more than 90%.After filtering BALF with 200 order steel meshes, washing 2 times, resuspended with the RPMI21640 culture medium, adjust cell concentration to 5 * 10
6/ ml, the same peripheral blood lymphocytes of subsequent treatment.
Four, cytokine assay: adopt double-antibody sandwich enzyme linked immunosorbent assay (ELISA) to measure, concrete grammar is according to description operation in the ELISA test kit.IFN-γ, IL-4, IL-5 and test kit are available from Pharmingen company, and test kit sensitivity is 28pg/mL.
The result:
Table 2 bronchoalveolar lavage fluid cytokines measurement (x ± s)
| n | IFN-γ(pg/mL) | IL-4(pg/mL) | IL-5(pg/mL) | |
| The A group | 8 | 269±86 | 110±51 | 150±51 |
| The B group | 8 | 920.00±134.36 ** | 77.20±9.2 ** | 21.35±6.9 ** |
| The C group | 8 | 766.87±105 ** | 132.00±6.7 ** | 142.8±3.8 ** |
| The D group | 8 | 323±43 | 875±116.7 | 975±124.7 |
B, C group and D group are relatively
*P＜0.01, statistics are analyzed with the SPSS statistical software
Experimental result shows: the secretion of the visible TH2 type of asthmatic model rat IL-4, IL-5, cytokine obviously is offset to the TH2 type.The serratia marcescens Seedling can obviously promote the secretion of TH1 type IFN-γ.
The result:
By above disclosed animal model, cytology's detection, cytokines measurement as seen:
1. after injecting the serratia marcescens Seedling in advance, can prevent the generation of rat sensitization asthmatic model.
Asthma experimental animal model EOS (eosinophilic granulocyte) is obviously more than other each groups, and prompting trachea allergic inflammation changes; PC50 is starkly lower than other each groups, and prompting trachea reactivity increases.BALF medium-sized lymphocyte showed increased after the immunity of Serratieae Seedling, the bronchovesicular medium-sized lymphocyte may be subjected to obvious activation; EOS and PC50 and experiment contrast group comparing difference do not have significance, illustrate that Serratieae Seedling treatment back all do not have the evidence of asthma on pathology and pathophysiology, illustrate inject the serratia marcescens Seedling in advance after, can prevent the generation of rat sensitization asthma.
2. cytokine assay shows, cytology research is found, the secretion of the visible TH2 type of asthmatic model rat IL-4, IL-5, and cytokine obviously is offset to the TH2 type.The serratia marcescens Seedling can obviously promote the secretion of TH1 type IFN-γ.
Claims (1)
1. the application of Becterin of Serratia marcescens in preparation treatment bronchial asthma medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105695365A (en) * | 2016-03-28 | 2016-06-22 | 蔡剑前 | Serratia marcescens and application thereof in tumor inhibition |
| CN105726580A (en) * | 2016-03-28 | 2016-07-06 | 蔡剑前 | Application of serratia marcescens vaccine in preparing medicine for preventing and/or treating immune system functional defect diseases and diabetes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1297285C (en) * | 2002-06-05 | 2007-01-31 | 靳海 | Becterin of Serratia marcescens for curing |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105695365A (en) * | 2016-03-28 | 2016-06-22 | 蔡剑前 | Serratia marcescens and application thereof in tumor inhibition |
| CN105726580A (en) * | 2016-03-28 | 2016-07-06 | 蔡剑前 | Application of serratia marcescens vaccine in preparing medicine for preventing and/or treating immune system functional defect diseases and diabetes |
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