CN117530986A - Application of tortoise-deer kidney-tonifying pill in preparation of medicines for preventing and treating chronic obstructive pulmonary disease in stationary phase - Google Patents
Application of tortoise-deer kidney-tonifying pill in preparation of medicines for preventing and treating chronic obstructive pulmonary disease in stationary phase Download PDFInfo
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- CN117530986A CN117530986A CN202210919336.2A CN202210919336A CN117530986A CN 117530986 A CN117530986 A CN 117530986A CN 202210919336 A CN202210919336 A CN 202210919336A CN 117530986 A CN117530986 A CN 117530986A
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- tortoise
- pill
- tonifying
- deer kidney
- chronic obstructive
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Abstract
The invention relates to application of a tortoise-deer kidney-tonifying pill in preparing a medicine for preventing and treating chronic obstructive pulmonary disease in a stationary phase. The turtle-deer kidney-tonifying pill can improve the quality of life, lung function, lung tissue inflammation and airway remodeling pathological changes of a model rat in the stationary phase of chronic obstructive pulmonary disease caused by LPS combined cigarette smoke exposure, reduce the number of inflammatory cells in alveolar lavage fluid, inhibit the generation and release of inflammatory factor IL-8, regulate the balance of MMPs/TIMPs systems, and has obvious treatment effect on chronic obstructive pulmonary disease. Tortoise and deer kidney tonifying pill can also be prepared into other preparation with the same formula for tonifying kidney.
Description
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to application of a tortoise-deer kidney-tonifying pill in preparing a medicine for preventing and treating chronic obstructive pulmonary disease in a stationary phase.
Background
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) is a common respiratory disease characterized by sustained and progressive airflow limitation, often accompanied by respiratory symptoms such as cough, expectoration, chest distress, etc., and smoking is the leading environmental causative factor. The morbidity and the mortality of the traditional Chinese medicine composition are extremely high, and the 5 th burden of global diseases and the 4 th cause of global death are occupied at present. The pathogenesis of chronic obstructive pulmonary disease is closely related to chronic inflammatory responses of the airways, lung parenchyma and pulmonary blood vessels and protease and anti-protease imbalance of the lungs.
At present, the modern medicine is mainly treated by medicaments such as glucocorticoid, bronchodilator (such as beta 2-receptor agonist), antibiotics and the like, and the long-term application of the medicaments is easy to cause antibiotic resistance and related medicament adverse reactions, and the medicaments for safely and effectively delaying the decline of the lung function and preventing the development of COPD are still lacking. Traditional medicine believes that COPD is located in the lung, its roots in the kidneys and closely related to the spleen.
A Chinese medicinal preparation, GUILUBUSHEN pill, is prepared from colla Plastri Testudinis (parched), colla Cornus Cervi (parched), radix rehmanniae Preparata, herba Epimedii (steamed), semen Cuscutae (parched), herba Cynomorii (steamed), radix Dipsaci (steamed), rhizoma Cibotii (steamed), radix Polygoni Multiflori Preparata, fructus Rosae Laevigatae (steamed), rubi fructus (steamed), radix astragali Preparata, semen Ziziphi Spinosae (parched), radix Glycyrrhizae Preparata, pericarpium Citri Tangerinae (steamed), and rhizoma Dioscoreae (parched), and has effects in strengthening tendons and bones, invigorating qi and blood, and tonifying kidney. The traditional Chinese medicine composition is mainly used for treating physical weakness, mental fatigue, soreness and weakness of waist and legs, dizziness, nocturnal enuresis, amnesia and insomnia. However, no research and report on the application of the tortoise-deer kidney-tonifying pill in preparing medicines for preventing and treating chronic obstructive pulmonary diseases are found so far.
Disclosure of Invention
Based on the above, the invention aims to overcome the defects of the prior art and provide the application of the tortoise-deer kidney-tonifying pill in preparing the medicine for preventing and treating the chronic obstructive pulmonary disease in the stationary phase, and the medicine has no obvious side effect.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
application of GUILU BUSHEN pill in preparing medicine for preventing and treating chronic obstructive pulmonary disease in stationary phase is provided.
The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing peripheral blood neutrophil percentage of animals in stationary phase of chronic obstructive pulmonary disease is provided.
The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing total white blood cell in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing neutrophil percentage in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing inflammatory factor IL-8 level in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
Application of GUILU BUSHEN pill in preparing medicine for regulating balance of MMPs/TIMPs system of animal body in stationary phase of chronic obstructive pulmonary disease is provided.
Application of GUILU BUSHEN pill in preparing medicine for improving inflammatory cell infiltration around bronchus of animal lung tissue in stationary phase of chronic obstructive pulmonary disease, alveolar structure disorder or pathological change of airway remodeling is provided.
The use of any one of the above, wherein the pill is replaced by GUILU BUSHEN oral liquid, GUILU BUSHEN Capsule, GUILU BUSHEN granule, or GUILU BUSHEN tablet.
The pharmaceutical formulation includes one or more pharmaceutically acceptable diluents, binders, lubricants, disintegrants or other excipients.
The invention has the beneficial effects that:
the tortoise-deer kidney-tonifying pill can improve the quality of life, lung function, lung tissue inflammation and airway remodeling pathological changes of a model rat in the stationary phase of chronic obstructive pulmonary disease caused by LPS (Lipopolysaccharide) combined with cigarette smoke exposure, reduce the number of inflammatory cells in alveolar lavage fluid, inhibit the generation and release of inflammatory factors IL-8, regulate the balance of MMPs/TIMPs systems, and has obvious treatment effect on chronic obstructive pulmonary disease.
Drawings
FIG. 1 is a graph showing weight comparison of Tortoise and deer Kidney-tonifying pill and model rats with stable period of chronic obstructive pulmonary disease of each control groupn＝10)
FIG. 2 is a graph of pathological morphology HE staining of lung tissue of rats in a model of Tortoise and deer kidney tonifying pill and COPD stabilization period of each control group. (×100 times, observed under a mirror, HE); wherein A: normal control group; b: a model group; c: low dosage group of GUILU BUSHEN pill; d: dosage group in Tortoise and deer Kidney-tonifying pill; e: high dosage group of GUILU BUSHEN pill; f: aminophylline groups; g: dexamethasone group; a-G are respectively the alveolar structure diagram of each group A-G
FIG. 3 is a microscopic view (100 x, under light microscope, MASSON) of collagen deposition on airway walls of rats in a model of a steady phase of chronic obstructive pulmonary disease in a tortoise deer kidney-tonifying pill and in each control group; wherein A: normal control group; b: a model group; c: low dosage group of GUILU BUSHEN pill; d: dosage group in Tortoise and deer Kidney-tonifying pill; e: high dosage group of GUILU BUSHEN pill; f: aminophylline groups; g: dexamethasone group
Detailed Description
The present invention will be described in further detail below, but embodiments of the present invention are not limited thereto.
The turtle-deer kidney-tonifying pill is prepared by adopting a preparation method of Chinese pharmacopoeia: 51g of salt semen cuscutae, 43g of epimedium herb (steamed), 43g of teasel root (steamed), 51g of cynomorium songaricum (steamed), 64g of rhizoma cibotii (steamed), 43g of semen zizyphi spinosae (fried), 64g of prepared polygonum multiflorum, 21g of honey-fried licorice root, 21g of dried orange peel (steamed), 9g of deer-horn gum (fried), 64g of prepared rehmannia root, 13g of tortoise-plastron glue (fried), 51g of cherokee rose fruit (steamed), 43g of honey-fried astragalus root, 43g of Chinese yam (fried) and 85g of raspberry (steamed), sixteen above materials are crushed into fine powder, and a pharmaceutically acceptable diluent, an adhesive, a lubricant, a disintegrating agent or other auxiliary materials are added, sieved and uniformly mixed. Adding water into 40g of refined honey per 100g of powder to make pill, drying, and making into water-honeyed pill; or adding 100-110 g of refined honey to prepare big honeyed pills.
The preparation method of other dosage forms with the same formulation as the Tortoise and deer kidney tonifying pill:
the Tortoise and deer kidney tonifying capsule is prepared by taking a standard Chinese medicinal prescription preparation (seventeenth volume) WS3-B-3230-98 of the Ministry of health of the people's republic of China: 128g of semen cuscutae (stir-fried), 106g of epimedium (steamed), 106g of teasel root (steamed), 128g of cynomorium songaricum (steamed), 160g of rhizoma cibotii (steamed), 106g of semen zizyphi spinosae (stir-fried), 160g of prepared polygonum multiflorum, 53g of honey-fried licorice root, 53g of dried orange peel (steamed), 23g of deer-horn gum (stir-fried), 160g of prepared rehmannia root, 34g of tortoise-shell glue (stir-fried), 128g of cherokee rose fruit (steamed), 106g of honey-fried astragalus root, 106g of Chinese yam (stir-fried) and 213g of raspberry (steamed), and crushing the above sixteen ingredients of dried orange peel, chinese yam, honey-fried licorice root, deer-horn gum and tortoise-shell glue into fine powder and uniformly mixing; decocting the rest materials in water twice for 2 hr for 1 hr, filtering, mixing filtrates, concentrating into soft extract, drying, grinding into fine powder, mixing with above fine powder, grinding with pharmaceutically acceptable diluent, binder, lubricant, disintegrating agent or other adjuvants, sieving, mixing, and making into 1000 granule.
The tortoise-deer kidney tonifying tablet is prepared by adopting a preparation method of national food and drug administration standard YBZ 05732008: 128g of semen cuscutae (stir-fried), 106g of epimedium (steamed), 106g of teasel root (steamed), 128g of cynomorium songaricum (steamed), 160g of rhizoma cibotii (steamed), 106g of semen zizyphi spinosae (stir-fried), 160g of prepared polygonum multiflorum, 53g of honey-fried licorice root, 53g of dried orange peel (steamed), 23g of deer-horn gum (stir-fried), 160g of prepared rehmannia root, 34g of tortoise-shell glue (stir-fried), 128g of cherokee rose fruit (steamed), 106g of honey-fried astragalus root, 106g of Chinese yam (stir-fried) and 213g of raspberry (steamed), and crushing the above sixteen ingredients of dried orange peel, chinese yam, honey-fried licorice root, deer-horn gum and tortoise-shell glue into fine powder and uniformly mixing; decocting the rest materials in water twice for 2 hr for the first time and 1 hr for the second time, filtering, mixing filtrates, concentrating into soft extract, drying, grinding into fine powder, mixing with above fine powder, sieving, mixing, granulating, drying, adding pharmaceutically acceptable diluent, binder, lubricant, disintegrating agent or other adjuvants, making into 1000 tablet, and coating film.
The preparation method of the tortoise-deer kidney-tonifying granule comprises the following steps: 128g of semen cuscutae (stir-fried), 106g of epimedium (steamed), 106g of teasel root (steamed), 128g of cynomorium songaricum (steamed), 160g of rhizoma cibotii (steamed), 106g of semen zizyphi spinosae (stir-fried), 160g of prepared polygonum multiflorum, 53g of honey-fried licorice root, 53g of dried orange peel (steamed), 23g of deer-horn gum (stir-fried), 160g of prepared rehmannia root, 34g of tortoise-shell glue (stir-fried), 128g of cherokee rose fruit (steamed), 106g of honey-fried astragalus root, 106g of Chinese yam (stir-fried) and 213g of raspberry (steamed), and crushing the above sixteen ingredients of dried orange peel, chinese yam, honey-fried licorice root, deer-horn gum and tortoise-shell glue into fine powder and uniformly mixing; decocting the rest materials in water for 2 hr for 1 hr, filtering, mixing filtrates, concentrating into soft extract, drying, grinding into fine powder, mixing with above fine powder, grinding, sieving, optionally adding pharmaceutically acceptable diluent, binder, lubricant, disintegrating agent or other adjuvants, mixing, and making into granule with 5-10 g per bag.
The tortoise-deer kidney-tonifying oral liquid is prepared by crushing 128g of semen cuscutae (stir-fried), 106g of epimedium (steamed), 106g of teasel root (steamed), 128g of cynomorium songaricum (steamed), 160g of rhizoma cibotii (steamed), 106g of semen ziziphi spinosae (stir-fried), 160g of prepared fleece-flower root, 53g of honey-fried licorice root, 53g of dried orange peel (steamed), 23g of deer-horn gum (stir-fried), 160g of prepared rehmannia root, 34g of tortoise-shell gum (stir-fried), 128g of cherokee rose fruit (steamed), 106g of honey-fried astragalus root, 106g of Chinese yam (stir-fried) and 213g of raspberry (steamed), crushing the dried orange peel, chinese yam, honey-fried licorice root, deer-horn gum and tortoise-shell gum into fine powder, uniformly mixing, adding 20-80% ethanol to extract twice; the other eleven materials such as semen cuscutae are decocted in water for two times, the first time is 2 hours, the second time is 1 hour, the filtering is carried out, the filtrates are combined, the water is added for dilution to 10000ML, and the mixture is split into 10ML per bottle.
Example 1
The kidney tonifying pill of tortoise plastron and deer has the effect of preventing and treating chronic obstructive pulmonary disease (hereinafter abbreviated as COPD) model rats in a stationary phase caused by LPS (Lipopolysaccharide) combined smoke exposure.
Preparation method of model for chronic obstructive pulmonary disease stabilization period
The rat model of chronic obstructive pulmonary disease was replicated by means of intratracheal injection of LPS in combination with cigarette smoke exposure. On day 1 and day 14, anaesthetized rats were injected intraperitoneally with 10mL/kg of 3% chloral hydrate, fixed in the supine position, a high intensity light source was placed on the surface of the neck of the rats, light was allowed to pass through the skin and muscle of the neck to illuminate the throat of the rats, round bright spots were observed at the airway opening, a 18-gauge venous indwelling needle was inserted into the trachea rapidly when the rats were inhaling the gas phase, whether the intubation was successful was judged according to the evaluation criteria of success of the intubation (vapor adherence due to respiration in the catheter or placement of a fine cilia at the mouth of the catheter, visible swing of cilia with respiration), after the intubation was successful, the trocar was withdrawn, 200 μl (1 mg/mL concentration) of physiological salt-dissolved LPS was accurately aspirated by a 1mL syringe, and a small amount of air was injected through the cannula to ensure that all the drug solution entered the trachea, the cannula was withdrawn, immediately the rat head was upright and moderately shaken for 2min to distribute the drug solution in the lung tissue as evenly as possible, and after the rats were awake and fed back into the rat cages. Normal groups were infused with normal saline.
On days 2-56 (except day 14, lipopolysaccharide is not smoked when day) rats are placed into a self-made animal smoking box (the size is about 60cm multiplied by 50cm multiplied by 40 cm), a small fan is arranged at the bottom of the side surface of the box, a rubber plug capable of fixing cigarettes is arranged outside the fan, 8 cigarettes are sequentially lighted by opening the fan, smoke is pumped into the smoking box, and 2 rows of small holes with the diameter of 0.5cm are arranged at the other side of the box (for ventilation and oxygen content guarantee). And (3) observing and recording the smoke concentration 1 time every 10min by a CO concentration detector arranged in the organic glass fumigating box, keeping the concentration of CO in the organic glass fumigating box within the range of 700-900PPM for 30min, opening the organic glass fumigating box cover after 30min, taking out the rats, and putting the rats into a raising cage. Such smoking is performed 2 times per day, once in the morning and afternoon, at intervals of more than 4 hours (30 min/time, 2 times/day, 4 hours/time).
(II) grouping and administration of animals
SPF-class SD male rats, 70, weighing 180+ -20 g, were supplied by the medical laboratory animal center in Guangdong province, and were randomly divided into 7 groups after 7d of adaptive feeding: normal control group, model group, low dose group of Tortoise deer Kidney pill, high dose group of Tortoise deer Kidney pill, dexamethasone group and aminophylline group, each group of 10. On the 29 th day of molding, the high, medium and low dosage groups of the tortoise-deer kidney-tonifying pill are subjected to gastric lavage for 7.2g/kg,3.6g/kg,1.8g/kg and 1 time/d 1 hour before smoking every day; the positive pharmaceutical group was administered by gavage 1h before each day, with dexamethasone at a dose of 0.3mg/kg and aminophylline at a dose of 30mg/kg,1 time/d. Normal control and model groups were given equal volumes of saline for intragastric administration for 4 weeks.
(III) sample acquisition and detection
1. Evaluation of body surface signs and behavioral tests
The symptoms of rats such as cough, asthma, nasal and respiratory secretions, etc. were recorded at weeks 4 and 8, and the scores are shown in table 1. The body weight of each rat was weighed and recorded every three days from the beginning of the molding. At week 8, open field experiments were performed, and the animal behavior analysis system was used to analyze the moving images recorded by the cameras within 5 minutes of each rat, and to analyze the behavioral indicators related to total distance walked and average walking rate.
Table 1 rat body surface characterization scale
2. Pulmonary function detection
On the 57 th day of the experiment, the animals are firstly placed in a closed whole-body plethysmograph to adapt to the environment for 10-15 minutes, and a bias flow meter of a front panel of a host machine is adjusted to 0.8L/min so as to prevent the animals from choking. After the animal was acclimatized, the conditions were recorded for 15 minutes in the free state, and respiratory parameters such as peak expiratory flow (peak expiratory flow, PEF), peak inspiratory flow (peak inspiratory flow, PIF), ventilation per minute (minute ventilation volume, MV), and expiratory flow (expiratory flow rate at 50%tidal volume,EF50) when 50% of the tidal volume was exhaled were measured.
3. HE staining for observing pathological changes of rat lung tissue
After the end of the experiment, rats were sacrificed. Right lung lower leaf tissue was fixed in 4% paraformaldehyde for 24 hours, dehydrated, embedded and sectioned. The sections were dewaxed conventionally to water, stained with hematoxylin for 15min, then ethanol-HCl differentiated for 2s, and then washed with running water for 15min before eosin staining for 2min. Washing with flowing water, adding low-concentration to high-concentration alcohol until dehydrated by absolute alcohol, sealing with xylene, and observing pathological changes of lung tissue under microscope.
4. Emphysema evaluation
Pathological sections after HE staining were observed under a microscope to find the appropriate magnification, and the number of lung intervals (NS) of the cross-shaped line in the center of the field of view was counted. The total length (L) of the reticle is measured, and the L/NS gives the MLI value, which can reflect the average alveolar diameter. The number of alveoli (Na) in each field is counted, divided by the area of this field to obtain a MAN value, which reflects the alveolar density. During measurement, bronchi and blood vessels are avoided, 5 visual fields are measured for each slice, and the magnification of each visual field is the same, so that the average value is obtained.
5. MASSON staining to observe airway collagen deposition changes
After the end of the experiment, rats were sacrificed by anesthesia. Right lung lower leaf tissue was fixed in 4% paraformaldehyde for 24 hours, dehydrated, embedded and sectioned. The sections were dewaxed conventionally to water, stained with Weigert iron hematoxylin staining solution for 10min, differentiated with acidic ethanol differentiation solution for 5-15s, and washed with water. After the blue is returned to blue by the bluing liquid for 5min, the ponceau dyeing liquid is dyed for 8min, then the ponceau dyeing liquid is washed by phosphomolybdic acid and weak acid working liquid, 1min is dyed in the aniline blue dyeing liquid, 95% ethanol is quickly dehydrated to absolute ethanol, xylene is transparent, a neutral resin is sealed, and the change of airway collagen deposition is observed under a microscope. 3 relatively complete small airways under each rat slice are randomly selected, and the inner circumference of the airway wall is smaller than 1000 mu m (short length-diameter ratio is less than or equal to 2). Measurement of bronchial peripheral diameter (Pbm, μm), airway wall basement membrane peripheral collagen area (Wcol, μm) using color image analysis software 2 ) The small airway collagen thickness is measured by the unit length of collagen thickness (Wcol/Pbm, μm) 2 /μm).
(IV) results of experiments
1. Influence of Tortoise and deer Kidney-tonifying pill on body surface sign score of COPD (chronic COPD) stable period model rat
As shown in Table 2, at 8 weeks of molding (after 4 weeks of administration), the model group score increased (p < 0.01) compared with the normal control group, suggesting that the model group rats had changed life status, such as hair loss, listlessness. Compared with the model group, the tortoise-deer kidney-tonifying pill has reduced sign scores (p < 0.01) in each dosage group and aminophylline group and dexamethasone group. The high-dose body sign score in the tortoise-deer kidney-tonifying pill is obviously lower than that of a dexamethasone group (p is less than 0.01).
TABLE 2 influence of Tortoise and deer Kidney tonifying pill on surface sign score of rat model in COPD stationary phasen＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
2. influence of Tortoise and deer Kidney-tonifying pill on weight of model rat in COPD stable period
During the experiment, the body weight of the normal control group rats showed a continuously stable increasing trend, while the body weight of the model group rats was slowly increased after the model group rats were infected. After the administration, the weight of the dexamethasone group rats is obviously reduced, the rats are gradually stable after the 6 th week, and the weight of the other groups of rats is in a growing trend, but the weight increase amplitude of the rats is smaller than that of the normal control group (P is less than 0.01). Compared with the model group, the weight of the tortoise-deer kidney-tonifying pill in the high-dose group tends to be increased, but no obvious statistical difference (P is more than 0.05). The weight increase of each dosage group of the Tortoise and deer kidney tonifying pill is far greater than that of dexamethasone group (P is less than 0.01). See table 3 and figure 1 for details. FIG. 1 is a graph showing weight comparison of Tortoise and deer Kidney-tonifying pill and model rats with stable period of chronic obstructive pulmonary disease of each control groupn＝10)。
TABLE 3 influence of Tortoise and deer Kidney-tonifying pill on weight of COPD stationary phase model ratsn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
3. influence of Tortoise and deer Kidney-tonifying pill on behavior of model rat in COPD stabilization period
As shown in Table 4, the total distance travelled by rats in the model group was reduced, the average rate of travelled was reduced, and the difference was statistically significant (P < 0.05) as compared to the normal control group. Compared with the model group, the total walking distance of rats in the high-dose group of the tortoise-deer kidney-tonifying pill is increased, and the average walking speed is increased (P is less than 0.05). The total walking distance and average speed of the high-dose group of the Tortoise and deer kidney tonifying pill are obviously higher than those of the dexamethasone group (P is less than 0.05). The total walking distance and average walking speed of the aminophylline rats are higher than those of the normal control group, and the aminophylline rats have significant differences (P is less than 0.01), and the reason is presumed to be that aminophylline has side effects of exciting nerve centers, so that the behavioral activities of the rats are increased.
TABLE 4 influence of Tortoise and deer Kidney-tonifying pill on behavioral index of COPD ratn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
4. influence of Tortoise and deer Kidney-tonifying pill on pulmonary function of model rat in COPD stable period
As shown in Table 5, the model group MV, PEF, PIF, EF was reduced compared with the normal control group, and the differences were statistically significant (P < 0.01), indicating a decrease in respiratory function and poor airway patency, suggesting successful modeling of the COPD rat model. Compared with the model group, the low-dose group MV, PEF, EF of the tortoise-deer kidney-tonifying pill is increased, and each index of the medium-dose group MV, PEF, PIF, EF and the high-dose group MV, PEF, PIF, EF is obviously increased (P is less than 0.05 or P is less than 0.01). Compared with the model group, the aminophylline group PIF, PEF, MV, EF is obviously increased (P is less than 0.01), and each flow index of the dexamethasone group is not statistically different from that of the model group (P is more than 0.05). Each dosage group of the Tortoise and deer kidney tonifying pill is obviously increased (P is less than 0.01) compared with a dexamethasone group MV, PEF, EF. The dosage groups of the Tortoise and deer Kidney-tonifying pill and aminophylline are prompted to improve the rat airflow limited state of the model group, the respiratory function is improved, and the effect of the Tortoise and deer Kidney-tonifying pill on improving the lung function is better than that of dexamethasone.
TABLE 5 influence of Tortoise and deer Kidney tonifying pill on COPD stationary phase model rat Lung functionn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
6. influence of Tortoise and deer Kidney-tonifying pill on lung histopathological morphology of model rat in COPD stable period (HE staining)
FIG. 2 is a graph of pathological morphology HE staining of lung tissue of rats in a model of Tortoise and deer kidney tonifying pill and COPD stabilization period of each control group.
As shown in fig. 2, the lung tissue of the normal control group rat has no obvious inflammatory cell aggregation, the airway mucosa epithelium is complete, the tube wall is regular, no occlusion exists, and the pulmonary alveolus cavity is not pathologically enlarged. The cilia part of the rat bronchiole mucosa epithelium of the model group is adhered and falls off, secretion is visible to exude in the lumen, each layer of the tube wall is infiltrated by more inflammatory cells, the smooth muscle layer is obviously thickened, and the tube wall is accompanied by lymphatic folliculogenesis and mucous gland hyperplasia; the alveolar pores are enlarged, the alveolar septum is broken, and the elastic fiber network is destroyed. The low dosage group of the tortoise-deer kidney-tonifying pill has the advantages that secretion is exuded from part of the lumen of a rat, the cilia part of the mucosa epithelium is adhered and falls off, inflammatory cells infiltrate the wall of the rat, the smooth muscle layer has thickening phenomenon, part of alveolus septa are broken, and the expanded alveoli are mutually fused into the capsule lumens with different sizes. In the Tortoise and deer kidney tonifying pill, the cilia part of the mucosa epithelium of bronchiole of a high-dose group rat is adhered, a small amount of inflammatory cells infiltrate the wall of the rat, and part of alveolar spaces are irregularly enlarged, ruptured and fused. The cilia part of the bronchiole mucosa epithelium of the aminophylline group rat is adhered, a small amount of the cilia part falls off, obvious inflammatory cells are gathered around the tube wall, obvious thickening phenomenon of smooth muscle layers is not generated, and the alveolus holes are enlarged and the alveolus walls are thinned. No obvious inflammatory cell infiltration is seen around the bronchioles of the dexamethasone group rats, but the alveolar structure is disordered and the elastic fiber network is severely damaged.
7. Influence of Tortoise and deer Kidney-tonifying pill on pulmonary emphysema of model rats in COPD stable phase
As shown in Table 6, the average alveolar number per unit area (MAN) of lung tissue was significantly reduced in rats in the model group and the average lining interval (MLI) was significantly increased (P < 0.01) compared to the normal control group. Compared with the model group, the dosage groups of the tortoise-deer kidney-tonifying pill, the aminophylline group MAN is obviously increased, and the MLI is obviously reduced (P is less than 0.01). Compared with dexamethasone MAN, the dosage of GUILU BUSHEN pill has the advantages of remarkably increased dosage, and remarkably reduced MLI (P < 0.01). The dosage groups of the tortoise-deer kidney-tonifying pill and the aminophylline groups are indicated to effectively improve the emphysema of rats with COPD, and the tortoise-deer kidney-tonifying pill has better curative effect than dexamethasone.
TABLE 6 influence of Tortoise and deer Kidney tonifying pill on model rats MAN and MLI in COPD stationary phasen＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
8. effect of Tortoise and deer Kidney-tonifying pill on COPD (COPD) stabilization period model rat airway collagen deposition
The lung tissue of the normal control group rat had a small amount of blue collagen fibers around the small airway wall. Compared with the normal control group, the collagen fibers around the airway wall of the rat in the model group are obviously increased, and the collagen thickness per unit length is increased (P is less than 0.01). Compared with the model group, the thickness of airway wall collagen in the tortoise-deer kidney-tonifying pill, the high-dose group, the aminophylline group and the dexamethasone group is obviously reduced (P is less than 0.01); the low-dose group collagen thickness of the tortoise-deer kidney-tonifying pill has a tendency to decrease, but has no statistical significance. The pulmonary fibrosis degree of rats in each administration group was suggested to be reduced as compared with that in the model group. See table 7 and fig. 3 for details. FIG. 3 is a microscopic view of collagen deposition on airway walls of rats in the model of chronic obstructive pulmonary disease in the stationary phase of the respective control groups (100 x, observed under light microscope, MASSON)
TABLE 7 influence of Tortoise and deer Kidney tonifying pill on COPD stationary phase model rat airway wall collagen thicknessn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## P＜0.01
conclusion: the Tortoise and deer kidney tonifying pill has the effects of improving the life quality, improving the lung function and inhibiting the lung pathological damage on a COPD stable period model rat exposed by LPS combined with smog, and the curative effect of the Tortoise and deer kidney tonifying pill is better than that of dexamethasone.
Example two
The turtle-deer kidney-tonifying pill relieves or/and prevents the action mechanism of rats in the stationary phase of chronic obstructive pulmonary disease.
Preparation method of model for chronic obstructive pulmonary disease stabilization period
The rat model of chronic obstructive pulmonary disease was replicated by means of intratracheal injection of LPS in combination with cigarette smoke exposure. On days 1 and 14, anesthetized rats were intraperitoneally injected with 3% chloral hydrate at 10mL/kg, 200 μl (1 mg/mL concentration) of LPS was injected into the trachea, and normal saline was injected into the group. On days 2-56 (except day 14, lipopolysaccharide is not smoked when day) rats are placed into a self-made animal smoking box (the size is about 60cm multiplied by 50cm multiplied by 40 cm), a small fan is arranged at the bottom of the side surface of the box, a rubber plug capable of fixing cigarettes is arranged outside the fan, 8 cigarettes are sequentially lighted by opening the fan, smoke is pumped into the smoking box, and 2 rows of small holes with the diameter of 0.5cm are arranged at the other side of the box (for ventilation and oxygen content guarantee). And (3) observing and recording the smoke concentration 1 time every 10min by a CO concentration detector arranged in the organic glass fumigating box, keeping the concentration of CO in the organic glass fumigating box within the range of 700-900PPM for 30min, opening the organic glass fumigating box cover after 30min, taking out the rats, and putting the rats into a raising cage. Such smoking is performed 2 times per day, once in the morning and afternoon, at intervals of more than 4 hours (30 min/time, 2 times/day, 4 hours/time).
(II) grouping and administration of animals
SPF-class SD male rats, 70, weighing 180+ -20 g, were supplied by the medical laboratory animal center in Guangdong province, and were randomly divided into 7 groups after 7d of adaptive feeding: normal control group, model group, low dose group of Tortoise deer Kidney pill, high dose group of Tortoise deer Kidney pill, dexamethasone group and aminophylline group, each group of 10. On the 29 th day of molding, the high, medium and low dosage groups of the tortoise-deer kidney-tonifying pill are subjected to gastric lavage for 7.2g/kg,3.6g/kg,1.8g/kg and 1 time/d 1 hour before smoking every day; the positive pharmaceutical group was administered by gavage 1h before each day, with dexamethasone at a dose of 0.3mg/kg and aminophylline at a dose of 30mg/kg,1 time/d. Normal control and model groups were given equal volumes of saline for intragastric administration for 4 weeks.
(III) sample acquisition and detection
1. Peripheral blood collection
After the experiment is finished, 10ml/kg of 3% chloral hydrate is injected into the abdominal cavity to anesthetize the animal, after the completion, the rat is fixed in a supine position, the abdominal skin and the abdominal wall muscle of the rat are rapidly cut off along the body midline, the abdominal aorta is exposed, a disposable blood taking needle is used for puncturing the needle in parallel along the arterial direction, 1ml of blood is taken by an anticoagulation blood taking tube (EDTA), and the blood taking tube is immediately and gently shaken to avoid anticoagulation blood clots.
(1) Total white blood cell count of peripheral blood
The total number of leukocytes is detected on the anticoagulated whole blood using a fully automatic blood cell analyzer.
(2) Peripheral blood leukocyte differential count
7ul of anticoagulated blood is dripped on one end of a glass slide, a cover slip is held by a hand for quick smear, the smear is naturally dried, and white blood cell classification count is performed after staining with Rui-Giemsa. Each specimen was counted under a microscope for 100 cells, neutrophils, macrophages and lymphocytes were classified by cell morphology, and the percentages of each cell were calculated.
2. Alveolar Lavage Fluid (BALF) collection
At the end of the experiment, 10ml/kg of 3% chloral hydrate is injected into the abdominal cavity to anesthetize the animal, the right main bronchus is ligated, a T-shaped incision is made at the lower end of the neck trachea, trachea cannula is carried out, 2ml of precooled physiological saline is slowly injected into the left lung by using a 2ml syringe, alveolar lavage is repeated for 3 times, about 1ml of alveolar lavage liquid can be recovered, and BALF is centrifuged for 10min at 1000rpm at 4 ℃. Collecting supernatant, and preserving at-80deg.C.
(1) BALF Total white blood cell count
After centrifugation, the pellet was mixed with 0.1ml of physiological saline, 10. Mu.l of the cell suspension was counted by a blood cell counting plate, and the total number of cells in 4 cells of the counting plate was counted under a microscope at a low magnification. Total number of white blood cells = total number of 4 large cells/4 x 10000 per ml BALF.
(2) BALF white blood cell differential count
And taking 30 mu l of cell suspension liquid drop at the left end of an adhesion glass slide, holding a cover glass to contact the cell suspension, spreading the liquid drop in a straight shape, slightly smearing the liquid drop at a right speed, naturally drying the smears, and staining with Rui-Jim Sa. Each specimen was counted under a microscope for 100 cells, neutrophils, macrophages and lymphocytes were classified by cell morphology, and the percentages of each cell were calculated.
(3) Alveolar lavage fluid IL-8 and TNF-alpha content detection
Taking out the BALF supernatant from the refrigerating environment, balancing for 15-30min at room temperature, measuring the concentration of IL-8 and TNF-alpha by ELISA method, and performing the experimental steps according to the specification of ELISA kit.
(4) Alveolar lavage fluid MMP-9, MMP-12 and TIMP-1 content detection
Taking out the BALF supernatant from the refrigerating environment, balancing for 15-30min at room temperature, measuring the concentrations of MMP-9, MMP-12 and TIMP-1 by ELISA, and performing experimental steps according to the specification of an ELISA kit.
(IV) results of experiments
1. Influence of Tortoise and deer Kidney-tonifying pill on total number and classification of peripheral blood white blood cells of COPD (COPD) model rats in stationary phase
As shown in table 8, the percent neutrophils in the model group were significantly elevated (P < 0.01) compared to the normal control group. Compared with the model group, the percent of neutrophils in the high-dose group of the tortoise-deer kidney-tonifying pill is obviously reduced (P is less than 0.05). The total leukocyte count of the dexamethasone group is significantly reduced compared with that of the normal control group, and the neutrophil percentage is greatly increased (P < 0.01).
TABLE 8 influence of Tortoise and deer Kidney tonifying pill on total and classification of peripheral blood leukocytes of COPD stationary phase model ratsn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
2. effect of Tortoise and deer Kidney-tonifying pill on total and classification of white blood cells in BALF of COPD stationary phase model rat
As shown in Table 9, the total number of leukocytes in the model group and the percentage of neutrophils were significantly increased (P < 0.01) compared to the normal control group. Compared with the model group, the total number of white blood cells in the low-dose group of the tortoise-deer kidney tonifying pill is obviously reduced; the total number of the white blood cells of the medium-dose group and the high-dose group is obviously reduced, and the percentage of the neutrophils is obviously reduced (P is less than 0.05 or P is less than 0.01). Compared with the model group, the percentage of neutrophils in the aminophylline group is significantly reduced (P < 0.05). The total number of dexamethasone leukocytes was significantly reduced (P < 0.05). Compared with dexamethasone, the percent of neutrophils in the turtle and deer kidney tonifying pill is obviously reduced (P is less than 0.05).
TABLE 9 influence of Tortoise and deer Kidney tonifying pill on total and classified counts of BALF white blood cells of COPD stationary phase model ratsn＝10)/>
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## p is less than 0.01; in comparison with the dexamethasone group, the preparation method, ▲ P＜0.05， ▲▲ P＜0.01
3. effect of Tortoise and deer Kidney-tonifying pill on IL-8 and TNF-alpha content in BALF of COPD stationary phase model rat
As shown in Table 10, IL-8 and TNF- α were significantly elevated in BALF in the model group compared to the normal control group, and the differences were statistically significant (P < 0.01, P < 0.05). Compared with the model group, the dosage group, aminophylline group and dexamethasone group IL-8 level in the Tortoise deer kidney tonifying pill are all obviously reduced (P is less than 0.05), and the three groups have no obvious difference. The IL-8 level of the low-dose group of the tortoise-deer kidney-tonifying pill has a reduced tendency, but has no obvious difference. Compared with the model group, the level of TNF-alpha in the aminophylline group is obviously reduced (P is less than 0.05).
TABLE 10 influence of Tortoise and deer Kidney tonifying pill on IL-8 and TNF-alpha content in BALF of COPD stationary phase model ratn＝10)
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## P＜0.01
4. effect of Tortoise and deer Kidney-tonifying pill on MMP-9, MMP-12 and TIMP-1 contents in BALF of COPD stationary phase model rat
As shown in Table 11, TIMP-1 levels were significantly elevated (P < 0.01) in the BALF in the model group compared to the normal control group. Compared with the model group, the levels of TIMP-1 in each dosage group of the tortoise-deer kidney-tonifying pill are obviously reduced (P is less than 0.01), wherein the level of TIMP-1 in the high dosage group is most obviously reduced. The TIMP-1 level of aminophylline group is obviously reduced (P is less than 0.01) compared with the model group.
Compared with the normal control group, the levels of MMP-9 and MMP-12 in the BALF of the model group of rats have a tendency to rise, but have no obvious statistical difference. Compared with the model group, the levels of MMP-12 in the various dosage groups and aminophylline groups of the tortoise deer kidney-tonifying pill are obviously reduced (P is less than 0.01).
TABLE 11 comparison of MMP-9, MMP-12, TIMP-1 levels in BALF of rats of each groupn＝10)/>
Note that: in comparison with the normal control group, * P＜0.05， ** p is less than 0.01; in comparison with the set of models, # P＜0.05， ## P＜0.01
conclusion: the turtle-deer kidney-tonifying pill can reduce the proportion of neutrophils in peripheral blood of COPD rats exposed by LPS combined smoke, and reduce the total number of white blood cells and the proportion of neutrophils in BALF; the dosage of the pill can inhibit the expression of inflammatory factor IL-8; tortoise and deer kidney tonifying pill can regulate balance of MMPs/TIMPs system by reducing expression of protease inhibitor TIMP-1 so as to improve airway remodeling.
The mechanism of action of the tortoise-deer kidney-tonifying pill for relieving/preventing COPD (COPD) in a model rat in a stationary phase may be related to reducing the number of inflammatory cells, inhibiting the generation and release of inflammatory factor IL-8 and improving airway remodeling.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. Application of GUILU BUSHEN pill in preparing medicine for preventing and treating chronic obstructive pulmonary disease in stationary phase is provided.
2. The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing peripheral blood neutrophil percentage of animals in stationary phase of chronic obstructive pulmonary disease is provided.
3. The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing total white blood cell in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
4. The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing neutrophil percentage in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
5. The application of Tortoise and deer kidney tonifying pill in preparing medicine for reducing inflammatory factor IL-8 level in alveolar lavage fluid of animals in stationary phase of chronic obstructive pulmonary disease is provided.
6. Application of GUILU BUSHEN pill in preparing medicine for regulating balance of MMPs/TIMPs system of animal body in stationary phase of chronic obstructive pulmonary disease is provided.
7. Application of GUILU BUSHEN pill in preparing medicine for improving inflammatory cell infiltration around bronchus of animal lung tissue in stationary phase of chronic obstructive pulmonary disease, alveolar structure disorder or pathological change of airway remodeling is provided.
8. The use according to any one of claims 1 to 7, wherein said tortoise-deer kidney-tonifying pill is replaced by a tortoise-deer kidney-tonifying oral liquid, or a tortoise-deer kidney-tonifying capsule, or a tortoise-deer kidney-tonifying granule, or a tortoise-deer kidney-tonifying tablet.
9. The use according to claim 8, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable diluents, binders, lubricants, disintegrants or other excipients.
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