CN110824173B - Application of angiogenesis promoting factor PDGFC (platelet-derived growth factor receptor) as marker for diagnosing and treating hepatopulmonary syndrome - Google Patents
Application of angiogenesis promoting factor PDGFC (platelet-derived growth factor receptor) as marker for diagnosing and treating hepatopulmonary syndrome Download PDFInfo
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Abstract
The invention discloses application of a angiogenesis promoting factor PDGFC in diagnosis and treatment of a hepatopulmonary syndrome marker, wherein the PDGFC is up-regulated in HPS blood and is possibly a molecule related to angiogenesis, the DGFC also has the performance of promoting proliferation, migration and tube formation of lung microvascular endothelial cells, and the lung injury score of an HPS group is obviously improved after PDGFC antibody is given, so the DGFC can be used as a medicine for promoting the generation of lung microvasculature, and an antibody specifically combined with the PDGFC can be used as a medicine for treating HPS, and is expected to be used for clinical intervention of HPS patients.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of a pro-angiogenic factor PDGFC serving as a marker for diagnosing and treating hepatopulmonary syndrome.
Background
Hepatopulmonary syndrome (HPS) is a pathological pulmonary microvascular dilatation (IPVD), neogenesis (Angiogenesis), and severe hypoxemia that occur on the basis of chronic liver diseases, and the incidence of the HPS in patients with liver cirrhosis can reach 15%, which is a main cause of perioperative lung infection and respiratory failure. Currently, an effective prevention and treatment means is still lacking clinically.
Pathological angiogenesis is one of the core changes in the HPS process, namely, wide expansion at the capillary level and new vessels cause mismatching of ventilation and perfusion, limited oxygen exchange diffusion function and arteriovenous shunt, and meanwhile, the expanded capillaries have small reaction on endogenous and exogenous vasoconstriction factors due to lack of smooth muscle cells, so that the traditional treatment effect is poor; the research shows that the indomethacin, the tamoxifen, the somatostatin and sympathomimetic drugs, the beta receptor blocker and the like do not show exact effects. Therefore, finding key pro-angiogenic factors is an important strategy for effective treatment of HPS.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a Platelet-derived growth factor C (PDGFC) for use as a marker for diagnosing and treating hepatopulmonary syndrome; the second purpose of the invention is to provide the application of PDGFC in preparing the medicament for promoting the generation of pulmonary microvasculature; the invention also aims to provide application of the antibody specifically binding to PDGFC in preparation of medicines for treating hepatopulmonary syndrome.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the application of the angiogenesis promoting factor PDGFC as a marker for diagnosing and treating the hepatopulmonary syndrome.
2. Application of angiogenesis promoting factor PDGFC in preparing medicament for promoting pulmonary microvascular formation.
Preferably, the angiogenesis promoting factor PDGFC is applied to the preparation of medicaments for proliferating lung microvascular endothelial cells.
Preferably, the application of the angiogenesis promoting factor PDGFC in preparing the medicament for migration of lung microvascular endothelial cells is provided.
Preferably, the angiogenesis promoting factor PDGFC is applied to preparing the medicines for forming the lung microvascular endothelial cells into tubes.
3. Application of an antibody specifically binding to a pro-angiogenic factor PDGFC in preparation of a medicament for treating hepatopulmonary syndrome.
Preferably, the antibody is a polyclonal antibody or a monoclonal antibody.
The invention has the beneficial effects that: the invention utilizes a proteomics method to screen molecules which are high in abundance in the blood of an HPS model rat and are possibly related to angiogenesis, and researches show that the screened angiogenesis promoting factor PDGFC can promote the proliferation, migration and tube formation of lung microvascular endothelial cells, so that the angiogenesis promoting factor PDGFC can be used as a medicine for promoting the generation of lung microvascular cells. The lung injury score of HPS group is obviously improved after the PDGFC antibody is given, so the antibody which specifically binds to PDGFC can be used as a medicament for treating HPS.
Drawings
In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:
FIG. 1 is an iTRAQ proteomics analysis of proteins differentially expressed in HPS rat serum (A: heat map analysis of differentially expressed proteins; B: differential expression of proteins at different time points).
FIG. 2 shows that PDGFC can promote angiogenesis (A: KI67 staining analysis shows that PDGFC overexpression can promote lung microvascular endothelial cell proliferation; B: Transwell experiment analysis shows that PDGFC overexpression can promote lung microvascular endothelial cell migration; and C: endothelial cell tube formation experiment shows that PDGFC overexpression can promote lung microvascular endothelial cell tube formation).
FIG. 3 shows PDGFC polyclonal antibody intervention in HPS rats (A: dosing regimen; B: rat lung HE staining; C: pathology score of rat lung HE staining; D: rat arterial blood oxygen partial pressure; E: analysis of rat arterial carbon dioxide partial pressure).
Detailed Description
The present invention is further described with reference to the following drawings and specific examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention.
Example 1 screening of pro-angiogenic factors
A proteomics method is used for screening molecules which are high in abundance and possibly related to angiogenesis in blood of an HPS model rat, and the specific method is as follows:
(1) method for constructing hepatopulmonary syndrome rat model by using common bile duct ligation
The Common Bile Duct Ligation (CBDL) was used to construct the HPS rat model, 30 for each of the sham and surgical groups. SD male adult rats, 200-220g, adopt Common Bile Duct Ligation (CBDL) to construct HPS animal model. The control rats were opened only and no common bile duct was ligated. And (3) analyzing and judging the pulmonary microvascular dilatation degree: after the rats are weighed, 5% chloral hydrate is anesthetized according to the volume of 7 mL/g; the abdominal cavity was opened rapidly, the abdominal aorta was exposed and blood was drawn with a blood gas needle. After completion, the analysis was carried out quickly with a blood gas analyzer ABL 800(Radiometer Copenhagen); the abdominal aorta was used for blood sampling and the samples were used for proteomic analysis.
(2) iTRAQ proteomics analysis
Sample treatment: and removing salt ions in the collected serum samples of the HPS rat in the first week, the third week and the fifth week by using a desalting kit respectively, then adding the samples into the sample lysate, and dissolving the samples in a warm water bath at 30 ℃ for 1 hour to fully dissolve the protein. The solution was centrifuged at 15000g for 15min at room temperature and the supernatant was again centrifuged to remove the impurities sufficiently. The supernatant was the total protein solution of the tissue, which was stored in-80 ℃ freezer or directly used for iTRAQ analysis after packaging.
Protein concentration was determined by BCA method.
The results of iTRAQ labeling, 2D-LC-MSMS and reverse chromatography-Triple TOF analyses are shown in fig. 1, with 68 proteins up-regulated and 44 down-regulated. Wherein PDGFC is up-regulated 4.6-fold in HPS blood. And informatics analysis showed that the molecule is associated with angiogenesis.
Example 2 verification of the angiogenesis promoting function of PDGFC
Treating pulmonary microvascular endothelial cells by using a constructed PDGFC knockdown and over-expressed lentivirus (Follenzi A, Ailles LE, Bakovic S, Geuna M, Naldini L: Gene transfer by viral vectors is limited by nuclear translocation and restricted by HIV-1pol sequences. Nature genetics 2000,25(2): 217) 222.), and measuring the angiogenesis promoting function of the microvascular endothelial cells through the proliferation, migration and tube forming capabilities of the microvascular endothelial cells.
The cell proliferation experiment result (fig. 2, a) shows that the number of Ki67 positive cells in the PDGFC overexpression group is significantly higher than that in the control group, and the number of Ki67 positive cells in the PDGFC knock-down group is significantly lower than that in the control group, which indicates that PDGFC overexpression can promote the angiogenesis capacity of lung microvascular endothelial cells.
The cell migration experiment result (fig. 2, B) shows that the lung microvascular endothelial cell migration ability of the PDGFC overexpression group is significantly higher than that of the control group, and the lung microvascular endothelial cell migration ability of the PDGFC knockdown group is significantly lower than that of the control group, which indicates that PDGFC overexpression can promote the migration ability of the lung microvascular endothelial cell.
The cell tube forming experiment result (fig. 2, C) shows that the tube forming capability of the lung microvascular endothelial cells in the PDGFC overexpression group is significantly higher than that of the control group, and the tube forming capability of the lung microvascular endothelial cells in the PDGFC knockdown group is significantly lower than that of the control group, which indicates that PDGFC overexpression can promote the capacity of the lung microvascular endothelial cells to form blood vessels.
Example 3 preparation of polyclonal antibodies and evaluation of the Effect on the disease of HPS rats
First, PDGFC polyclonal antibodies were prepared. The method of preparing polyclonal antibodies was invented by the England scientists Milstein and Kohler in 1975 and thus received the Nobel prize in 1984. However, as is currently understood, there are no polyclonal antibodies, or antibody drugs/formulations, available on the market against PDGFC. Therefore, based on previous researches, the PDGFC polyclonal antibody is constructed and used for treating HPS rats, and is expected to be applied to HPS patients to achieve disease intervention.
Prepared polyclonal antibody of PDGFC is injected into HPS rats by tail vein injection, the single injection dose is 120 ml/day/kg, and the administration mode of 1 ml/kg/day is tail vein administration, as shown in A in figure 3. Dissections were performed three weeks after dosing and the results of the analysis were as follows:
the PDGFC multiple resistance treated group showed significantly better lung injury scores compared to the HPS group (B and C in fig. 3); in contrast, the multi-antibody treatment group showed significant recovery of both oxygen partial pressure and carbon dioxide partial pressure (D and E in FIG. 3) compared to the HPS group. This demonstrates that PDGFC polyclonal antibody treatment is a significant improvement over the typical symptoms of HPS.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitutions or changes made by the person skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (2)
1. An antibody specifically binding with angiogenesis promoting factor PDGFC is applied to the preparation of a medicament for treating hepatopulmonary syndrome.
2. Use according to claim 1, characterized in that: the antibody is a polyclonal antibody or a monoclonal antibody.
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