CN109646453B - Method for establishing and detecting liver injury endoplasmic reticulum stress differential expression model mouse - Google Patents
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Abstract
The invention provides a method for establishing and detecting a liver injury endoplasmic reticulum stress difference expression model mouse, and belongs to the technical field of animal models. Dividing BALB/c mice with the same sex, growth week age and weight into 2 groups, carrying out administration once on an acute group, carrying out administration twice on a chronic group every week, wherein the interval between the two administrations is 72h, and carrying out continuous administration for 12-16 weeks; after administration, 2 groups of mice were sacrificed and liver tissues of two groups of mice were extracted, respectively; measuring the expression levels of GRP78 and CHOP in liver tissues of mice respectively, and calculating the ratio of CHOP/GRP78 of the two groups; when the CHOP/GRP78 ratio of the chronic group is obviously higher than that of the acute group, the mice of the chronic group are liver injury endoplasmic reticulum stress differential expression model mice. The invention provides raw materials for researching acute and chronic liver injury and pathogenesis of disease progression, provides theoretical basis for prevention and treatment of clinical liver diseases, and has the advantages of simple method, high modeling success rate and good repeatability.
Description
Technical Field
The invention belongs to the technical field of animal model construction, and particularly relates to a method for establishing and detecting a liver injury endoplasmic reticulum stress differential expression model mouse.
Background
Liver damage is a clinical syndrome of liver function damage characterized by massive liver cell degeneration, necrosis, inflammatory cell infiltration, etc. in a short time due to various causes, and has a high mortality rate. The liver cell necrosis is a common pathological feature of various liver injuries and comprises: hepatocyte necrosis (necrosis), programmed necrosis (necroptosis), apoptosis (apoptosis) and autophagy (autophagy). The progress of the liver disease, namely the damage of the liver cells, is related to a plurality of factors, and under the action of various pathogenic factors, the liver cells maintain the intracellular environment through starting a plurality of protection mechanisms and promote the survival of the cells. Therefore, the damage resistance of the liver cells and the damage factors together determine the outcome of the liver disease.
The treatment method preferred by most patients with liver injury is medical comprehensive treatment, however, because of pathogenesisThe preparation is not clear, the treatment effect of the internal medicine is limited, and the death rate is 50-80%. The model for differential expression of endoplasmic reticulum stress of liver injury of experimental animals is an indispensable tool for researching pathogenesis of various liver diseases and screening therapeutic drugs. In recent years, methods for manufacturing experimental liver injury animal models at home and abroad mainly focus on chemical liver injury models and immunological liver injury models. The immune liver injury model is mostly modeled by adopting sword bean protein A (Con), lipopolysaccharide (BCG + LPS) and the like; the chemical liver injury model is mainly composed of carbon tetrachloride (CCl)4) D-galactosamine (D-Gal), ethanol, flavin, etc. In addition, a novel modeling method is disclosed in the prior art, for example, a patent of publication No. CN103735561A discloses that tunicamycin dimethyl sulfoxide solution is adopted as an endoplasmic reticulum stress inducer to perfuse a mouse, and animal model establishment is completed after administration for 8-48 h. However, this method does not give out whether the mice treated by the above administration method really form a mouse liver injury model, and the enzyme activities of AST and ALT in the liver of the administered mice are measured, liver weight and liver index are measured, and pathological sections are made.
Disclosure of Invention
In view of the above, the present invention aims to provide a novel method for establishing and detecting a liver injury endoplasmic reticulum stress differential expression model mouse, which is not only simple and convenient to operate, low in requirement on operators, but also high in modeling success rate.
The invention provides a method for establishing and detecting a liver injury endoplasmic reticulum stress difference expression model mouse, which comprises the following steps:
1) randomly selecting BALB/c mice with the same sex, similar growth week age and weight to be divided into 2 groups, and dividing the mice into an acute group or a chronic group according to a drug administration method; the acute group was administered once and mice were sacrificed 24h after administration; the chronic group is administrated twice a week, the interval time of the two administrations is 72 hours, and the mice are sacrificed after the continuous administration for 12-16 weeks; the administered medicine is endoplasmic reticulum stress inducer;
2) respectively extracting liver tissues of the two groups of mice in the step 1) to obtain liver tissues of acute groups of mice and liver tissues of chronic groups of mice;
3) measuring the expression levels of GRP78 and CHOP in the liver tissues of the acute group of mice and the chronic group of mice respectively, and calculating the ratio of the acute group CHOP/GRP78 and the ratio of the chronic group CHOP/GRP 78;
4) analyzing the change of the CHOP/GRP78 ratio of the acute group compared with the CHOP/GRP78 ratio of the chronic group, when the CHOP/GRP78 ratio of the chronic group is obviously higher than the CHOP/GRP78 ratio of the acute group, the mice of the chronic group are mice of a model with differential expression of endoplasmic reticulum stress caused by liver injury.
Preferably, the endoplasmic reticulum stress-inducing agent in step 1) is CCl4Olive oil mixed solution; the CCl4CCl in olive oil mixed solution4The volume ratio of the olive oil to the olive oil is 1: 3-5.
Preferably, said CCl4The dosage of the olive oil mixed solution is 5-10 ml/Kg mouse.
Preferably, the method for determining the expression levels of GRP78 and CHOP in the liver tissue of the acute group of mice and the liver tissue of the chronic group of mice in the step 3) comprises the steps of forming a band by using Western blotting on GRP78 or CHOP, determining the gray value of GRP78 or CHOP band, and expressing the ratio of the acute CHOP/GRP78 expression level and the chronic CHOP/GRP78 expression level by using the ratio of the gray values of the CHOP and the GRP 78.
Preferably, the weight of BALB/c mice in step 1) comprises 23-27 g.
Preferably, no less than 8 BALB/c mice per group in the acute or chronic group in step 1). The invention provides a method for establishing and detecting a liver injury endoplasmic reticulum stress differential expression model mouse, which is divided into acute group liver injury and chronic group liver injury according to administration time, and is an experimental animal model for liver injury endoplasmic reticulum stress differential expression which is not mentioned in the prior art, and then the expression of GRP78 and CHOP protein is detected as a core evaluation index, wherein GRP78 protein is a survival promoting marker protein, the expression of which indicates that liver injury is better, and CHOP protein is an apoptosis marker protein, and the expression of which indicates that liver injury is worse; meanwhile, the judgment standard for successfully establishing the liver injury endoplasmic reticulum stress differential expression model mouse is set as that when the chronic group CHOP/GRP78 ratio is obviously higher than the acute group CHOP/GRP78 ratio, the chronic group mouse is the liver injury endoplasmic reticulum stress differential expression model mouse. The method provided by the invention has the characteristic of 100% detection accuracy, provides a new thought for establishing the endoplasmic reticulum stress differential expression model mouse with liver injury, provides an experimental tool for researching acute and chronic liver injury and pathogenesis of disease progression, and provides a theoretical basis for prevention and treatment of clinical liver diseases.
Meanwhile, the establishing and detecting method provided by the invention has the advantages of low condition requirement, simplicity and convenience in method, good stability, high modeling success rate, good repeatability and the like; western blot is used for detecting expression levels of GRP78 and CHOP, and the method has the characteristics of simple operation and good repeatability.
Drawings
FIG. 1 shows the establishment of CCl in the example4A flow chart for inducing the endoplasmic reticulum stress differential expression of the model mouse;
FIG. 2 is a graph showing the results of Western blotting (Western blot) and a statistical chart of the model groups in examples;
FIG. 3 is a bar graph showing the expression levels of GRP78 and CHOP proteins and CHOP/GRP78 values in the model groups of examples.
Detailed Description
The invention provides a method for establishing and detecting a liver injury endoplasmic reticulum stress difference expression model mouse, which comprises the following steps:
1) randomly selecting BALB/c mice with the same sex, similar growth week age and weight to be divided into 2 groups, and dividing the mice into an acute group or a chronic group according to a drug administration method; the administration method of the acute group is that the administration frequency is once, and the mice are killed 24 hours after the administration; the chronic group is administrated twice a week, the interval time of the two administrations is 72 hours, and the mice are killed after the continuous administration for 12-16 weeks; the administered medicine is endoplasmic reticulum stress inducer;
2) respectively extracting liver tissues of the two groups of mice in the step 1) to obtain liver tissues of acute groups of mice and liver tissues of chronic groups of mice;
3) measuring the expression levels of GRP78 and CHOP in the liver tissues of the acute group of mice and the chronic group of mice respectively, and calculating the ratio of the acute group CHOP/GRP78 and the ratio of the chronic group CHOP/GRP 78;
4) analyzing the change of the CHOP/GRP78 ratio of the acute group compared with the CHOP/GRP78 ratio of the chronic group, when the CHOP/GRP78 ratio of the chronic group is obviously higher than the CHOP/GRP78 ratio of the acute group, the mice of the chronic group are mice of a model with differential expression of endoplasmic reticulum stress caused by liver injury.
The invention provides a method for dividing BALB/c mice of the same sex, similar growth week age and body weight into 2 groups randomly, and dividing the mice into an acute group or a chronic group according to a drug administration method; the administration method of the acute group is that the administration frequency is once and 24 hours after the administration; the chronic group is administrated twice a week, the interval time of the two administrations is 72 hours, and the continuous administration lasts for 12-16 weeks; the administered drug is an endoplasmic reticulum stress inducer.
In the present invention, the endoplasmic reticulum stress-inducing agent is preferably CCl4Olive oil mixed solution; the CCl4CCl in olive oil mixed solution4The volume ratio of the olive oil to the olive oil is preferably 1: 3-5, and more preferably 1: 4. The CCl4The olive oil mixed solution is preferably filtered through a 0.22 micron filter. The CCl4The dosage of the olive oil mixed solution is preferably 5-10 ml/Kg mouse.
In the present invention, the administration method preferably comprises the steps of: the injection needle is penetrated into the lower abdomen of the mouse at a position which is about 0.5cm away from the abdominal white line, the injection needle is pushed forward 3-5 cm along the subcutaneous part, then the needle head and the abdomen of the mouse form an angle of about 30 degrees to penetrate into the abdominal cavity, the penetrating speed of the needle head is high, the needle head is introduced into the abdominal cavity when the resistance feeling disappears, the needle head generally does not exceed 1cm after entering the abdominal cavity, the head of the mouse is in a low position during injection, the tail part of the mouse is slightly lifted, the viscera are moved forward, and the injection into the viscera is avoided. At this point the formulated CCl is injected4Mixing the olive oil solution to giveFood is forbidden before medicine for 12 h.
In the present invention, the weight of BALB/c mice preferably comprises 23-27 g. In the acute or chronic group, it is preferable that not less than 8 BALB/c mice per group are used.
After injection, 2 groups of BALB/c mice are killed, and two groups of mouse liver tissues are respectively extracted to obtain acute group mouse liver tissues and chronic group mouse liver tissues.
In the present invention, the method of sacrifice is preferably sacrifice by cervical dislocation after removing the eyeball to drain blood. The method for extracting liver tissue comprises the following steps: dissolving 50mg of fresh liver tissue blocks in 5ml of lysate, fully and uniformly grinding by using a homogenizer, centrifuging for 5min at the rotating speed of 12000r/min under the condition of 4 ℃, extracting supernatant and mixing with protein loading buffer solution in a volume ratio of 4: 1, and boiling for 3-5 min by boiling water to obtain the liver injury protein.
After obtaining the liver injury protein, the invention respectively measures the expression level of GRP78 and CHOP in the liver tissue of the acute group of mice and the liver tissue of the chronic group of mice, and calculates the ratio of acute group CHOP/GRP78 and the ratio of chronic group CHOP/GRP 78.
In the invention, the levels of the survival promotion marker protein (GRP78) and the apoptosis marker protein (CHOP) are detected by using a Western blot standard process. GRP78 indicates liver regeneration, and CHOP indicates apoptosis, both of which are intrinsic to the liver, and when the liver is stressed by the endoplasmic reticulum, their expression changes, suggesting that the progression of liver disease in mice becomes better or worse. The expression levels of GRP78 and CHOP are preferably detected by Western blotting (Western blot), and the gray value of GRP78 or CHOP protein bands of each group is determined, and the ratio of CHOP/GRP78 of the acute group and the ratio of CHOP/GRP78 of the chronic group are expressed as the ratio of the gray value of CHOP to GRP78 of each group.
After the ratio of the acute group CHOP/GRP78 to the chronic group CHOP/GRP78 is obtained, the invention analyzes the change of the ratio of the acute group CHOP/GRP78 to the chronic group CHOP/GRP78, and when the ratio of the chronic group CHOP/GRP78 is obviously higher than the ratio of the acute group CHOP/GRP78, the chronic group mouse is a liver injury endoplasmic reticulum stress differential expression model mouse. When the CHOP/GRP78 ratio of the chronic group is obviously higher than that of the acute group CHOP/GRP78, the method prompts the enhancement of endoplasmic reticulum stress apoptosis-promoting reaction of the chronic liver injury, and completes the establishment and detection of a liver injury endoplasmic reticulum stress differential expression model mouse.
In order to obtain accurate detection results, the above experimental steps are preferably repeated 3 times. As seen from the activity reaction of the mice, the acute group of mice has normal activity and reaction, normal food intake, stable respiration and no death, while the chronic group of mice has activity, slow reaction, poor food intake, ascites and even death; from FIG. 2, it can be seen that CCl for injection4Olive oil mixed solution 24h, GRP78 and CHOP expression are increased, CCl is injected4When the olive oil mixed solution is used for 12-16 weeks, the expression of GRP78 is not obviously changed, the CHOP expression is obviously increased, and compared with the change of the CHOP/GRP78 ratio, the CHOP/GRP78 ratio of the chronic liver injury group is obviously higher than that of the acute liver injury group (P is less than or equal to 0.05), which indicates that the endoplasmic reticulum stress apoptosis promotion reaction of the chronic liver injury is enhanced, and the difference conversion from a survival promotion signal to an apoptosis promotion signal exists.
The method for establishing and detecting a liver injury endoplasmic reticulum stress differential expression model mouse provided by the invention is described in detail below with reference to the examples, but the method is not to be construed as limiting the scope of the invention.
Example 1
(1) Mouse selection
A batch of BALB/c mice weighing 23-27 g was purchased from a company and divided into three groups, each group consisting of 24 BALB/c mice, and the 24 BALB/c mice were divided into an acute group, a chronic group and a control group.
(2)CCl4Preparation of olive oil mixed solution
1ml of CCl4Fully dissolved in 4ml of olive oil, filtered by a 0.22 micron bacteria filter and stored at room temperature under aseptic conditions for later use.
(3) Administration group administration
Fasting was 12h prior to dosing. The administration method of the acute group is CCl injection4Olive oil mixed solution (CCl)4And olive oil in a volume ratio of 1: 4) once, and killing the mice by a cervical vertebra dislocation method after removing eyeballs and discharging blood after 24 hours of administration; the chronic group is administrated twice a week, the interval time of the two administrations is 72h, and the continuous administration is carried out for 12-16 weeksAfter administration, the mice were sacrificed by cervical dislocation after removal of the eyeball to drain the blood; the control group was not administered and the mice were sacrificed by cervical dislocation after removal of the eyeball to drain the blood. The method of administration is as follows: the injection needle is penetrated into the lower abdomen of the mouse at a position which is about 0.5cm away from the white abdominal line, the injection needle is pushed forward 3-5 cm along the subcutaneous part, then the needle head and the abdomen of the mouse form an angle of about 30 degrees and penetrate into the abdominal cavity, the penetrating speed of the needle head is high, the needle head is inserted into the abdominal cavity when the resistance feeling disappears, the needle head is indicated to be inserted into the abdominal cavity, the needle head entering the abdominal cavity is generally not more than 1cm, the head of the mouse is in a low position during injection, the tail of the mouse is slightly lifted, the viscera are moved forward, and.
4) Extractant assay for marker proteins
After injecting the medicine for 24 hours and 12-16 weeks, killing the mice by a cervical dislocation method after removing eyeballs and discharging blood, taking 50mg of fresh liver tissue blocks, dissolving the fresh liver tissue blocks in 5ml of lysate, fully and uniformly grinding the lysate by using a homogenizer, centrifuging the lysate for 5min (12000r/min) at 4 ℃, extracting supernatant and protein upper sample buffer solution, mixing the supernatant and the protein upper sample buffer solution in a volume ratio of 4: 1, and boiling the mixture in boiling water for 3-5 min. Levels of a survival promotion marker protein (GRP78) and an apoptosis marker protein (CHOP) are detected according to a Western blot method standard process, wherein GRP78 represents liver regeneration, CHOP represents apoptosis, the two are owned by the liver, when the liver is under endoplasmic reticulum stress, the expression of the liver and the endoplasmic reticulum stress can be changed, the mouse liver disease process is prompted to be improved or deteriorated, and the beta-Acatin protein is used as an internal reference. The change in the CHOP/GRP78 ratio was compared by analyzing the gray values of the corresponding protein bands, as detected by Western blotting (Western blot). The above experiment was repeated 3 times. The results are shown in Table 1.
TABLE 1 expression level of different time-marker proteins
Statistical analysis is carried out on the CHOP/GRP78 mean values of the acute group and the chronic group, and the CHOP/GRP78 ratio of the chronic liver injury group is obviously higher than that of the acute liver injury group (P is less than or equal to 0.05), so that the enhancement of endoplasmic reticulum stress apoptosis promotion reaction of the chronic liver injury is prompted, and the establishment and the detection of the liver injury endoplasmic reticulum stress differential expression model mouse are completed.
As seen from the activity reaction of the mice, the acute group of mice has normal activity and reaction, normal food intake, stable respiration and no death, while the chronic group of mice has activity, slow reaction, poor food intake, ascites and even death; from FIG. 2, it can be seen that CCl for injection4Olive oil mixed solution 24h, GRP78 and CHOP expression are increased, CCl is injected4When the olive oil mixed solution is used for 12-16 weeks, the expression of GRP78 is not obviously changed, the CHOP expression is obviously increased, and compared with the change of the CHOP/GRP78 ratio, the CHOP/GRP78 ratio of the chronic liver injury group is obviously higher than that of the acute liver injury group (P is less than or equal to 0.05), which indicates that the endoplasmic reticulum stress apoptosis promotion reaction of the chronic liver injury is enhanced, and the difference conversion from a survival promotion signal to an apoptosis promotion signal exists.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (4)
1. A method for establishing a liver injury endoplasmic reticulum stress differential expression model mouse is characterized by comprising the following steps:
1) randomly selecting BALB/c mice with the same sex, similar growth week age and weight to be divided into 2 groups, and dividing the mice into an acute group or a chronic group according to a drug administration method; the acute group was administered once and mice were sacrificed 24h after administration; the chronic group is administrated twice a week, the interval time of the two administrations is 72 hours, and the mice are sacrificed after the continuous administration for 12-16 weeks; the administered medicine is endoplasmic reticulum stress inducer;
the endoplasmic reticulum stress inducer is CCl4Olive oil mixed solution; the CCl4CCl in olive oil mixed solution4The volume ratio of the olive oil to the olive oil is 1: 3-5; the CCl4The dosage of the olive oil mixed solution is 5-10 ml/Kg of mouse;
2) respectively extracting liver tissues of the two groups of mice in the step 1) to obtain liver tissues of acute groups of mice and liver tissues of chronic groups of mice;
3) measuring the expression levels of GRP78 and CHOP in the liver tissues of the acute group of mice and the chronic group of mice respectively, and calculating the ratio of the acute group CHOP/GRP78 and the ratio of the chronic group CHOP/GRP 78;
4) analyzing the change of the CHOP/GRP78 ratio of the acute group compared with the CHOP/GRP78 ratio of the chronic group, when the CHOP/GRP78 ratio of the chronic group is obviously higher than the CHOP/GRP78 ratio of the acute group, the mice of the chronic group are mice of a model with differential expression of endoplasmic reticulum stress caused by liver injury.
2. The method of claim 1, wherein the step 3) of determining the expression level of GRP78 and CHOP in liver tissue of acute group and chronic group comprises using Western blotting to band GRP78 or CHOP, determining the gray scale value of GRP78 or CHOP band, and expressing the ratio of CHOP/GRP78 expression level in acute group and CHOP/GRP78 expression level in chronic group as the ratio of the gray scale value of CHOP to GRP 78.
3. The method of claim 1 or 2, wherein the weight of BALB/c mice in step 1) comprises 23-27 g.
4. The method of claim 3, wherein no less than 8 BALB/c mice per group are present in the acute or chronic group in step 1).
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| CN108904570A (en) * | 2018-07-23 | 2018-11-30 | 遵义医学院附属医院 | A kind of acute liver damage inducer and its application |
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| CN103735561A (en) * | 2014-01-15 | 2014-04-23 | 蚌埠医学院 | Establishment method of endoplasmic reticulum stress induced mouse acute liver injury model |
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