阅读说明：本技术 泮托拉唑在制备防治肝纤维化的药物中的应用 (Application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis ) 是由 庹必光 文国容 李靖国 朱加兴 刘雪梅 谢睿 龙晓英 徐靖宇 金海� 安家兴 于 2019-08-19 设计创作，主要内容包括：本发明提供了泮托拉唑在制备防治肝纤维化的药物中的应用,属于药物新用途技术领域,所述泮托拉唑抑制了促纤维化细胞因子TGFβ(转化生长因子β)的受体TGFβR1的表达,抑制了肝脏星状细胞的活化,抑制肝细胞上皮间质的转化,从而抑制肝纤维化的发生。(The present invention provides application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis, belong to technical field of new application of medicine, the Pantoprazole inhibits the expression for promoting the receptor TGF β R1 of brotic cells factor TGF β (transforming growth factor β), inhibit the activation of hepatic stellate cell, the conversion for inhibiting liver cell Epithelial and stromal, to inhibit the generation of liver fibrosis.)

1. application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.

2. application of the Pantoprazole in the drug that preparation inhibits Hepatic Stellate Cell Activation.

3. application of the Pantoprazole in the drug of preparation prevention and treatment hepatic injury.

4. application according to claim 3, which is characterized in that the hepatic injury is caused by carbon tetrachloride.

5. Pantoprazole inhibits the application in the increased drug of hepatic tissue collagenous fibres in preparation.

6. application of the Pantoprazole in the drug that preparation inhibits the expression of extracellular matrix protein.

7. application according to claim 6, which is characterized in that the extracellular matrix protein includes that α-smooth muscle moves egg One or more of white, COL1A1 albumen and fibronectin.

8. application of the Pantoprazole in the drug that preparation increases the expression of epithelial phenotype albumen.

9. application of the composition containing Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.

10. described in any item applications according to claim 1~9, which is characterized in that the dosage form of the drug includes capsule, ball Agent, tablet, granule or injection.

Technical field

The invention belongs to technical field of new application of medicine more particularly to Pantoprazole in the medicine for preparing prevention and treatment liver fibrosis Application in object.

Background technique

Liver fibrosis is the precursor of cirrhosis, is the necessary pathological process that various chronic liver diseases develop to cirrhosis.Root According to existing result of study, generally believe that cirrhosis is irreversible chronic progressive hepatopathy, and liver fibrosis is invertibity Pathological change.Therefore, inhibit liver fibrosis occurrence and development be the key that prevent chronic liver disease development be cirrhosis, to liver The research for the treatment of of fibrosis has important clinical meaning.

Liver fibrosis shows as liver extracellular matrix ingredient and excessively deposits singularly, Chronic Liver caused by a variety of causes It is dirty to damage the occurrence and development that all can lead to liver fibrosis, and then develop into cirrhosis.The common reason of liver fibrosis is mainly disease Virus hepatitis, Alcoholic or nonalcoholic fatty liver, oneself immunity hepatitis etc..Theoretically, best to prevent liver fibrosis The method of formation is the adverse factor of removal damage liver.Really, effective antiviral therapy can prevent the shape of liver fibrosis At and progress, but to most of progressive stage Alcoholics and nonalcoholic fatty liver and heredity and autoimmune liver disease disease People, removal damage factor are difficult.People are being dedicated to studying the cellular elements machine that liver fibrosis occurs always in recent years System, it is desirable to be able to which discovery prevention prevents or reverse liver fibrosis progression, improves the method for liver function.Although, it has been found that very More compounds test in vitro and have effect of anti hepatic fibrosis in animal model, but these compounds are clinically few Effect.The treatment liver fibrosis such as current clinically useful hormone, ursodesoxycholic acid, his class D drug, but there is no satisfied anti- The only effect that liver fibrosis forms and is in progress.Therefore, finding its effective drug for inhibiting liver fibrosis occurrence and development is still There is an urgent need to.Liver fibrosis be liver damage factor long term as a result, its occurrence and development be one there are many cell, The complicated process that various kinds of cell signaling molecule participates in, is related to the effect of various kinds of cell molecular mechanism.With fibrocyte in liver Abnormal accumulation, extracellular matrix ingredient over-deposit and inflammatory disorders and structure disturbance be characterized.Hepatic stellate cell (hepatic stellate cells, HSC) activation be considered liver fibrosis starting, in terms of play key Effect.Many factors include inflammatory cytokine and chemotactic factor (CF), transforming growth factor β, blood vessel derivative growth factor, oxidation The occurrence and development for being involved in liver fibrosis stress be waited.

Proton pump inhibitor Pantoprazole inhibits gastric mucosa parietal cell H because of it⁺-K⁺- ATPase is to gastric acid secretion inhibiting Effect, be clinically widely used for the treatment of gastric acid related disease (such as peptic ulcer) at present.

But so far, do not find that proton pump inhibitor Pantoprazole is preventing and treating answering in hepatic fibrosis medicines With.

Summary of the invention

In view of this, the answering in the drug of preparation prevention and treatment liver fibrosis the purpose of the present invention is to provide Pantoprazole With providing the new application of Pantoprazole.

In order to achieve the above-mentioned object of the invention, the present invention provides following technical schemes:

The present invention provides application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.

The present invention also provides application of the Pantoprazole in the drug that preparation inhibits Hepatic Stellate Cell Activation.

The present invention also provides application of the Pantoprazole in the drug of preparation prevention and treatment hepatic injury.

Preferably, the hepatic injury is caused by carbon tetrachloride.

The present invention also provides Pantoprazoles to inhibit the application in the increased drug of hepatic tissue collagenous fibres in preparation.

The present invention also provides application of the Pantoprazole in the drug that preparation inhibits the expression of extracellular matrix protein.

Preferably, the extracellular matrix protein includes the smooth actin of α-, COL1A1 albumen and fibronectin One or more of.

The present invention also provides application of the Pantoprazole in the drug that preparation increases the expression of epithelial phenotype albumen.

The present invention also provides application of the composition containing Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.

Preferably, the dosage form of the drug includes capsule, pill, tablet, granule or injection.

The present invention provides application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis, the Pantoprazole suppression The expression for promoting the receptor TGF β R1 of brotic cells factor TGF β is made, it is suppressed that the activation of hepatic stellate cell inhibits liver thin The conversion of born of the same parents' Epithelial and stromal, to inhibit the generation of liver fibrosis.

Detailed description of the invention

Fig. 1 is proton pump inhibitor Pantoprazole to hepar damnification in hepatic fibrosis in mice model caused by carbon tetrachloride Histological change influence, for liver histological by HE chromoscopy, the representative of hepatic tissue HE chromoscopy is shown in figure Property image, the liver of normal mouse has a leaflet structure for normally having central vein, and liver cell does not regenerate in streak, After giving carbon tetrachloride, liver is shown in inflammatory cell infiltration, necrosis of liver cells, lobuli hepatis structure disorder, hepatic cell cords disorder, There is regenerated liver cell.Different degrees of mitigation, especially Pantoprazole are shown in the damage of Pantoprazole (PPZ) each group mouse liver 5mg/kg and 10mg/kg group, it is seen that normal hepatic cell cords and lobuli hepatis；

Fig. 2 is Masson dyeing detection proton pump inhibitor Pantoprazole to hepatic fibrosis in mice caused by carbon tetrachloride The influence of hepatic tissue Collagen fiber deposition in model, upper part are the representative image of Masson dyeing, and lower part is The comparison in each group Masson stained positive region (i.e. collagenous fibres amount), (Control group) hepatic tissue after giving carbon tetrachloride Collagen fiber deposition obviously increase, Pantoprazole (PPZ) inhibits collagenous fibres caused by carbon tetrachloride in dose-dependant Deposition, compared with normal group,^$$P<0.01；Compared with the control group,^#P<0.01 P>0.05, * P<0.05, * *；

Fig. 3 is Sirius Red dyeing detection proton pump inhibitor Pantoprazole to the fibre of Mouse Liver caused by carbon tetrachloride The influence of hepatic tissue Collagen fiber deposition in dimensionization model, upper part are the representative image of Sirius Red dyeing, under Face is divided into the comparison in each group Sirius Red stained positive region (i.e. collagenous fibres amount), after giving carbon tetrachloride The Collagen fiber deposition of (Control group) hepatic tissue obviously increases, and Pantoprazole (PPZ) inhibits tetrachloro in dose-dependant The deposition for changing collagenous fibres caused by carbon, compared with normal group,^$$P<0.01；Compared with the control group,^#P>0.05, * P< 0.05, * P < 0.01 *；

Fig. 4 is proton pump inhibitor Pantoprazole in hepatic tissue in hepatic fibrosis in mice model caused by carbon tetrachloride TGF beta receptor TGF β R1, extracellular matrix protein α-SMA, COL1A1 and Fibronectin and liver cell epithelial phenotype E- The influence of cadherin expression, by the expression of Western Blot analysis detection protein, the A in Fig. 4 is representative egg White print image, the B-F in Fig. 4 are the comparison of the protein expression of each group, (Control group) liver after giving carbon tetrachloride The expression of TGF β R1, α-SMA, COL1A1 and Fibronectin of tissue obviously increase, and the expression of E-cadherin obviously subtracts Few, Pantoprazole (PPZ) inhibits the expression of TGF β R1, α-SMA, COL1A1 and Fibronectin in dose-dependant, and The expression for increasing E-cadherin, compared with normal group,^$$P<0.01；Compared with the control group, P < 0.01 * P < 0.05, * *；

Fig. 5 is for TGF β to hepatic stellate cells LX2 cell activation and Pantoprazole to hepatic stellate cells base caused by TGF β The influence of matter protein expression is first handled LX2 cell 48 hours with TGF β, then is acted on carefully with the Pantoprazole (PPZ) of various dose Born of the same parents 24 hours, by the expression of Western Blot analysis detection protein, the A in Fig. 5 was representative western blot figure Picture, the B-D in Fig. 5 are the comparison of the protein expression of each group, TGF β processing significantly result in LX2 cell α-SMA, COL1A1 and Fibronectin expression increase, Pantoprazole (PPZ) reduce in dose-dependant α-SMA caused by TGF β, COL1A1 and Fibronectin expression increases, compared with no TGF β group,^$$P<0.01；Compared with adding control group with TGF β,^#P> P < 0.01 0.05, * P < 0.05, * *；

Fig. 6 is the shadow that proton pump inhibitor Pantoprazole leads to LX2 cell activation and cellular matrix protein expression to TGF β It rings, is first handled LX2 cell 30 minutes with the Pantoprazole (PPZ) of various dose, then handled LX2 cell 24 hours with TGF β, led to The expression of Western Blot analysis detection protein is crossed, the A in Fig. 6 is representative western blot image, the B-D in Fig. 6 For the comparison of the protein expression of each group, Pantoprazole (PPZ) inhibited in dose-dependant α-SMA caused by TGF β, COL1A1 and Fibronectin expression increases, compared with no TGF β group,^$$P<0.01；Compared with control plus TGF β group,^#P> P < 0.01 0.05, * P < 0.05, * *.

Specific embodiment

The present invention provides application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.In the present invention, described The dosage form of drug preferably includes capsule, pill, tablet, granule or injection.The present invention is to Pantoprazole in the drug The auxiliary material and auxiliary material content of content and use are not particularly limited, using the conventional supplementary product kind for preparing various dosage forms and using With supplementary product consumption, using in various dosage forms routinely containing the content of active material.System of the present invention to the drug Preparation Method is not particularly limited, using the customary preparation methods of regular dosage form.

The present invention also provides application of the Pantoprazole in the drug that preparation inhibits Hepatic Stellate Cell Activation.In this hair In bright, the dosage form of the drug preferably includes capsule, pill, tablet, granule or injection.The present invention is in the drug The content of Pantoprazole and the auxiliary material of use and auxiliary material content are not particularly limited, and prepare various dosage forms uses using conventional Supplementary product kind and supplementary product consumption, using in various dosage forms routinely containing the content of active material.The present invention is to institute The preparation method for stating drug is not particularly limited, using the customary preparation methods of regular dosage form.

The present invention also provides application of the Pantoprazole in the drug of preparation prevention and treatment hepatic injury.In the present invention, described Hepatic injury is preferably caused by carbon tetrachloride.In the present invention, the dosage form of the drug preferably include capsule, pill, tablet, Granula or injection.The present invention is to the content of Pantoprazole in the drug and the auxiliary material of use and auxiliary material content without spy It is different to limit, the supplementary product kind and supplementary product consumption that various dosage forms use are prepared using conventional, using routinely containing in various dosage forms The content of active substance.The present invention is not particularly limited the preparation method of the drug, using the normal of regular dosage form Regulation Preparation Method.

The present invention also provides Pantoprazoles to inhibit the application in the increased drug of hepatic tissue collagenous fibres in preparation.In In the present invention, the dosage form of the drug preferably includes capsule, pill, tablet, granule or injection.The present invention is to the medicine The content of Pantoprazole and the auxiliary material of use and auxiliary material content are not particularly limited in object, prepare various dosage forms using conventional The supplementary product kind and supplementary product consumption used, using in various dosage forms routinely containing the content of active material.The present invention The preparation method of the drug is not particularly limited, using the customary preparation methods of regular dosage form.

The present invention also provides application of the Pantoprazole in the drug that preparation inhibits the expression of extracellular matrix protein. In the present invention, the extracellular matrix protein preferably includes the smooth actin of α-, COL1A1 albumen and fibronectin One or more of.In the present invention, the dosage form of the drug preferably includes capsule, pill, tablet, granule or injection Agent.The present invention is not particularly limited the content of Pantoprazole in the drug and the auxiliary material of use and auxiliary material content, uses It is conventional to prepare the supplementary product kind and supplementary product consumption that various dosage forms use, using routinely containing active material in various dosage forms Content.The present invention is not particularly limited the preparation method of the drug, using the conventional preparation side of regular dosage form Method.

The present invention also provides application of the Pantoprazole in the drug that preparation increases the expression of epithelial phenotype albumen.In In the present invention, the extracellular matrix protein is preferably included in α-smooth actin, COL1A1 albumen and fibronectin One or more.In the present invention, the dosage form of the drug preferably includes capsule, pill, tablet, granule or injection. The present invention is not particularly limited the content of Pantoprazole in the drug and the auxiliary material of use and auxiliary material content, using normal The supplementary product kind and supplementary product consumption that regulation uses for various dosage forms, using in various dosage forms routinely containing active material Content.The present invention is not particularly limited the preparation method of the drug, using the customary preparation methods of regular dosage form .

The present invention also provides application of the composition containing Pantoprazole in the drug of preparation prevention and treatment liver fibrosis.In In the present invention, the composition is preferably using Pantoprazole as sole active agent.In the present invention, the dosage form of the drug is excellent Choosing includes capsule, pill, tablet, granule or injection.Content and use of the present invention to Pantoprazole in the drug Auxiliary material and auxiliary material content be not particularly limited, prepare supplementary product kind that various dosage forms use and supplementary product consumption i.e. using conventional Can, using in various dosage forms routinely containing the content of active material.The present invention is to the preparation method of the drug without spy It is different to limit, using the customary preparation methods of regular dosage form.

The present invention is not particularly limited the application method of the drug, according to doctor's advice.

Technical solution provided by the invention is described in detail below with reference to embodiment, but they cannot be managed Solution is limiting the scope of the present invention.