Compound for treating hepatic cirrhosis portal hypertension and application thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a compound for treating cirrhosis portal hypertension and application thereof. The compound provided by the invention can be used for preparing medicines for treating cirrhosis portal hypertension. The medicine can achieve the treatment purposes of improving LSEC dysfunction and reducing portal pressure of cirrhosis on the basis of not influencing circulating pressure.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a compound for treating liver cirrhosis portal hypertension and its application. Background Art

[0002] Liver cirrhosis portal hypertension (PH) refers to the pathological increase in portal vein pressure due to increased hepatic vascular resistance and congestion of portal vein system blood caused by chronic end-stage liver disease. Portal hypertension is a driving factor for a series of liver cirrhosis complications, such as ascites, gastrointestinal bleeding, hepatorenal syndrome, hepatic encephalopathy, etc. It is the pathological basis for a series of complications. Cirrhotic patients with portal hypertension complications often have poor prognosis, are repeatedly admitted to the hospital, and are described as unstable decompensated cirrhosis.

[0003] Dysfunction of liver sinusoidal endothelial cells (LSECs) is a key factor leading to and exacerbating portal hypertension. However, the mechanism of LSEC dysfunction is still unclear. Deeply exploring the disease mechanism of the occurrence and development of liver cirrhosis portal hypertension is of great significance for the treatment and prognosis improvement of cirrhotic patients. Summary of the Invention

[0004] The present invention mainly aims at the above technical problems, and provides a drug for reducing the production of ROS in liver sinusoidal endothelial cells, and / or increasing the activity of eNOS in liver sinusoidal endothelial cells, and / or treating liver cirrhosis portal hypertension, and its preparation method.

[0005] The present invention provides the following technical solutions:

[0006] In a first aspect, the present invention provides a drug for reducing the production of ROS in liver sinusoidal endothelial cells, and / or increasing the activity of eNOS in liver sinusoidal endothelial cells, and / or treating liver cirrhosis portal hypertension, characterized in that the drug comprises a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0007] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or non-specifically block the complement activation of the terminal pathway.

[0008] In another aspect, another object of the present invention is to provide the application of a complement inhibitor in the preparation of a drug for reducing the production of ROS in liver sinusoidal endothelial cells.

[0009] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0010] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0011] On the other hand, another object of the present invention is to provide the use of a complement inhibitor in the preparation of a drug for increasing the eNOS activity of hepatic sinusoidal endothelial cells.

[0012] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0013] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0014] On the other hand, another object of the present invention is to provide the use of a complement inhibitor in the preparation of a drug for treating liver cirrhosis portal hypertension.

[0015] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0016] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0017] On the other hand, the present invention provides a method for preparing a drug for reducing the production of ROS in hepatic sinusoidal endothelial cells, characterized in that the method comprises using a complement inhibitor as an active ingredient to prepare the drug.

[0018] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0019] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0020] On the other hand, the present invention provides a method for preparing a drug for increasing the eNOS activity of hepatic sinusoidal endothelial cells, characterized in that the method comprises using a complement inhibitor as an active ingredient to prepare the drug.

[0021] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0022] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0023] On the other hand, the present invention provides a method for preparing a drug for treating liver cirrhosis portal hypertension, which is characterized in that the method includes preparing the drug with a complement inhibitor as an active ingredient.

[0024] Optionally, the aforementioned drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

[0025] Optionally, the aforementioned complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

[0026] Optionally, the drug in any of the aforementioned schemes may further contain other compounds or drugs for treating liver cirrhosis portal hypertension, such as non-selective β-blockers, vasodilators, somatostatin and its analogs, antibiotics, endothelin receptor antagonists, diuretics, terlipressin, etc.

[0027] Optionally, the excipient in any of the aforementioned schemes may be lactose, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, etc., for forming tablets or capsules. Or it may be mannitol, disodium hydrogen phosphate, sodium chloride, for preparing injection solutions or lyophilized powders.

[0028] Preferably, the complement inhibitor in any of the aforementioned schemes is a complement inhibitor capable of specifically blocking the complement activation of the classical pathway.

[0029] Preferably, the complement inhibitor in any of the aforementioned schemes is complement component 1 inhibitor (C1-INH).

[0030] The present invention has the following beneficial effects compared with the prior art:

[0031] 1. Most previous studies on the key etiology of liver cirrhosis portal hypertension, "cellular dysfunction of LSECs", have been carried out from the perspective of hemodynamics. This study for the first time found that complement activation in the portal vein promotes LSEC oxidative stress by inducing mitochondrial dysfunction of LSECs, and leads to LSECs dysfunction, thus participating in the development of portal hypertension. The pathogenic mechanism of complement participating in liver cirrhosis portal hypertension was explored and explained from the perspective of pathophysiology. The present invention for the first time proposes to treat liver cirrhosis portal hypertension by inhibiting complement activation in the portal vein.

[0032] 2. Further, the present invention discovers for the first time that complement inhibitors can improve LSEC dysfunction and reduce cirrhotic portal pressure without affecting the circulatory pressure by inhibiting complement activation in the portal vein. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The products, methods and their beneficial effects of the present invention will be described in detail below in conjunction with the drawings and specific embodiments.

[0034] Figure 1 is the transcriptomics of incubating human liver sinusoidal endothelial cells with portal vein serum (PVS) / heat-inactivated complement serum (HIS) from cirrhotic patients; wherein Figure A is a schematic diagram of the mitochondrial oxidative phosphorylation (OXPHOS) pathway, showing the expression of all components in the transcriptome; Figure B is a heat map of all components of the oxidative phosphorylation (hsa00190) pathway in decompensated patient PVS (Patient) and healthy control peripheral serum / peripheral HIS (Health); Figure C is the GSEA analysis (gene set enrichment analysis diagram) of the pathway expression of hsa00190 in the transcriptome;

[0035] Figure 2 is a heat map showing the down-regulation of the transcriptional levels of MT-ND series genes in the PVS treatment group.

[0036] Figure 3 is the detection result of intracellular ROS; wherein Figure A is the fluorescence signal of detecting ROS with a superoxide fluorescence probe; Figure B is the statistical result of the relative content of ROS, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001.

[0037] Figure 4 is the relative content of ROS after complement activation products stimulate LSECs, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001.

[0038] Figure 5 is the expression of ND1, 2, 4, 5, 6 at the transcriptional and protein levels after complement activation products stimulate LSECs; wherein Figures A to E are the inspection results of the transcriptional levels of ND1, 2, 4, 5, 6 respectively; Figure F is the detection result of the protein levels of ND1, 2, 4, 5, 6; * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001.

[0039] Figure 6 is the protein detection result of eNOS and PeNOS in LSECs after complement activation products; wherein Figure A is the treatment with C3a; Figure B is the treatment with C5a, and Figure C is the treatment with sC5b9.

[0040] Figure 7 It is the proportion of complement activation caused by different pathways in patients with decompensated liver cirrhosis.

[0041] Figure 8 It is the relative content of ROS after treatment with complement inhibitors (Figure A), and the protein expression of eNOS and peNOS (Figure B).

[0042] Figure 9 It is a schematic diagram of establishing a liver cirrhosis portal hypertension model using SD rats.

[0043] Figure 10 It is a photograph of the liver at different development stages of the rat liver cirrhosis portal hypertension model (Figure A), nodular fibrosis of hepatocytes (Figure B), and the changes in body weight (Figure C), portal vein pressure (Figure D), alanine aminotransferase (Figure E), and aspartate aminotransferase (Figure F).

[0044] Figure 11 It is the change in the level of sC5b-9 in the portal vein at different development stages of the rat liver cirrhosis portal hypertension model; Figure A shows the change in intrahepatic MAC deposition; Figure B shows the change in the level of sC5b-9.

[0045] Figure 12 It is a schematic diagram of treating rats with liver cirrhosis portal hypertension using C1-INH.

[0046] Figure 13 It is the change in serum sC5b-9 level, portal vein pressure, arterial pressure, and heart rate after treatment with C1-INH.

[0047] Figure 14 It is the correlation analysis between portal vein sC5b-9 and portal vein pressure.

[0048] Figure 15 It is the ROS fluorescence intensity of rat LSECs before and after treatment with C1-INH.

[0049] Figure 16 It is a scanning electron microscope of the fenestrae on the surface of liver sinusoidal endothelial cells, observed after treating LSEC with complement activation products added to heat-inactivated healthy human peripheral serum.

[0050] Figure 17 It is a scanning electron microscope of the fenestrae on the surface of liver sinusoidal endothelial cells, observed after treating LSEC with complement inhibitors. Detailed implementation methods

[0051] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0052] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those of ordinary skill in the technical field to which this application belongs.

[0053] Example 1 Paired transcriptome analysis of portal vein serum (PVS) / heat-inactivated complement serum (HIS) from the same patient

[0054] Portal vein serum from 10 patients with decompensated liver cirrhosis due to portal hypertension was collected. Paired comparison was made between the portal vein serum (PVS) and heat-inactivated complement serum (HIS) of the same patient, and the transcriptomes of 10 pairs of patient sera incubated with human liver sinusoidal endothelial cells (LSECs) were analyzed.

[0055] Patient selection criteria: (a) Inclusion criteria (meeting simultaneously): Liver cirrhosis was diagnosed by tissue biopsy or at least two imaging examinations; TIPS surgery was planned for treatment due to various decompensation events (such as refractory ascites, bleeding from gastroesophageal varices, etc.); age ≥ 18 years and ≤ 85 years; the subject voluntarily participated in the study and had signed the informed consent form.

[0056] (b) Exclusion criteria (any one is sufficient): Those with a CTP grade of liver function > 14 points; those with liver cancer or extrahepatic tumors, severe important organ dysfunction, and other diseases affecting expected survival found during preoperative evaluation; those who underwent TIPS recanalization due to shunt failure; women planning to be pregnant, already pregnant, or breastfeeding; those who refused to sign the informed consent form.

[0057] Table 1 Information of the enrolled patients

[0058]

[0059] CHB: Chronic viral hepatitis; ALD: Alcoholic liver disease; NASH: Non-alcoholic steatohepatitis.

[0060] Using heat-inactivated complement serum (HIS) as the control group, genes with a fold change of 1.5 were used to screen for differential genes, and a total of 7,247 genes were found to have differences at the transcriptional level. KEGG pathway enrichment revealed multiple disease signaling pathways involved in the pathogenic mechanism of "mitochondrial dysfunction". Further analysis of the gene expression of mitochondrial oxidative phosphorylation (OXPHOS) found that the overall transcription of genes in the oxidative respiratory chain in the PVS treatment group was upregulated, indicating that the LSECs in the PVS treatment group may have abnormal activation and energy metabolism ( Figure 1)。In addition, complement activation treatment (portal vein serum <pvs>) downregulation of the MT-ND series of genes encoded by mitochondrial DNA in the group ( Figure 2 ), which suggests that complement activation may lead to oxidative stress and dysfunction of liver sinusoidal endothelial cells by causing downregulation of the expression of ND genes in the mitochondrial respiratory chain and mitochondrial dysfunction.

[0061] Example 2 Detection of mitochondrial ROS

[0062] To verify whether the portal vein serum of patients with complement activation can increase the production of reactive oxygen species in LSECs, a superoxide fluorescence probe was used to detect the production of ROS. It was found that after stimulating LSECs with the serum of patients with complement activation, compared with heat-inactivated serum (HIS) of complement, the intracellular ROS increased significantly ( Figure 3 A and 3B). This verified the transcriptomics finding that the portal vein serum with complement activation can cause an increase in the production of ROS in LSECs and cause cellular oxidative stress.

[0063] Example 3 Complement activation in portal vein serum induces oxidative stress in liver sinusoidal endothelial cells leading to endothelial dysfunction

[0064] 1. We previously found that C3a, C5a, and sC5b-9 were abnormally increased in the portal vein blood of patients with liver cirrhosis, and increased with the progression of the disease and the increase in portal vein pressure. In addition, it was also found that the complement activation product C5b-9 was specifically deposited in and around the portal vein. This prompted us that these cell damages might be the key role of the complement activation products C3a, C5a, and sC5b-9. Therefore, we further explored the effects of C3a, C5a, and sC5b-9 on cell respiration stimulation and ROS production.

[0065] LSECs cells were stimulated with different concentration gradients of anaphylatoxins C3a, C5a, and sC5b-9 for 4 hours respectively, and it was found that C3a, C5a, and sC5b-9 could all increase the production of intracellular ROS. ( Figure 4 ). This suggests that the three key complement activation components in the patient's serum can cause a decrease in the utilization rate of NO by increasing the ROS in liver sinusoidal endothelial cells and leading to cellular oxidative stress.

[0066] 2. To explore whether the increase in the production of ROS in LSECs cells caused by complement activation products is caused by a decrease in ND expression, LSECs were stimulated in vitro according to the highest concentrations of complement activation products C3a, C5a, and sC5b-9 detected in the portal vein blood of patients. It was found that the transcriptional levels of ND1, ND2, ND4, ND5, and ND6 in the cells were significantly downregulated compared with the control group (HNHS group) ( Figure 5 A - E), and consistent results were also observed in the protein levels of ND1, ND2, ND4, and ND6 in the cells ( Figure 5 F).

[0067] 3. The previous results suggest that complement activation products can increase cellular ROS production by downregulating the expression of ND protein in LSECs, and ROS can reduce eNOS activity by inhibiting the phosphorylation of endothelial nitric oxide synthase (eNOS), leading to endothelial cell dysfunction. After treating LSECs with different doses of complement activation products, we found that as the doses of C3a, C5a, and sC5b-9 increased, eNOS phosphorylation was inhibited (downregulation of peNOS expression) and eNOS activity decreased ( Figure 6 A-6C)

[0068] 4. In the portal vein blood of 10 patients with decompensated liver cirrhosis with portal hypertension detected using a complement detection kit (Eagle bio science series), complement activation caused by the classical pathway, alternative pathway, and lectin pathway accounted for 41%, 39%, and 20% respectively, and the total complement activation caused by the classical pathway and lectin pathway accounted for 61%( Figure 7 ).

[0069] 5. We designed a rescue experiment to verify whether the use of complement inhibitors could improve the oxidative stress and dysfunction of LSECs caused by complement activation. LSECs were treated with the portal vein serum of patients with complement activation, and different complement activation pathways were blocked respectively to examine the final ROS generation and eNOS activity

[0070] Specific inhibition strategies: Specific blockade of complement activation in the classical pathway and lectin pathway with complement factor C1 inhibitors (SerpinG1, C1-INH); specific blockade of alternative pathway activation with complement factor D inhibitor (CFD-INH).

[0071] Complete inhibition strategy: Complement factor C3 inhibitor (C3-INH) was used to nonspecifically block complement activation in the terminal pathway.

[0072] The results showed ( Figure 8 ) that the use of complement inhibitors could significantly reduce ROS production, and the C1-INH group had a more obvious effect on reducing ROS; complement inhibitors could increase the expression of peNOS, improve eNOS activity, and improve the endothelial dysfunction of LSECs. However, the improvement effect of hepatic sinusoidal endothelial function after C3-INH treatment was not as good as that of C1-INH, perhaps because physiological (low-level) complement activation can play a beneficial physiological role, such as promoting the regeneration and proliferation of damaged endothelial cells. Considering the finding of the complement activation pathway in the portal vein blood of patients - the complement activation caused by the classical pathway and lectin pathway exceeded 60%, these may be the reasons for the better therapeutic effect of C1-INH. C1-INH may improve liver cirrhosis portal hypertension by inhibiting complement activation in the classical and lectin pathways in the portal vein.

[0073] Example 4 C1-INH can reduce the portal vein pressure of liver cirrhosis with portal hypertension

[0074] 1. We selected SD rats to establish a liver cirrhosis with portal hypertension model. Carbon tetrachloride was repeatedly intraperitoneally injected into the rats each time, and the portal hypertension level was reached after 8 weeks of induction ( Figure 9 ).

[0075] The results showed ( Figure 10 ) that when CCL4 was repeatedly injected for 4 weeks, MASSON showed a small amount of irregularly proliferated hepatocytes in the liver, and a small amount of nodular fibrosis began to appear, accompanied by a small amount of fibrous tissue formation; at this time, the body weight of the rats in the modeling group began to decrease, the liver enzymes increased, and the portal vein pressure increased. When CCL4 was repeatedly injected for 6 weeks, MASSON showed more severe fibrosis, and false lobules began to appear in the liver. At this time, the hepatic tissue structure was significantly damaged. At this time, the body weight of the rats in the modeling group was still lower than that of the control group, and the liver enzymes and portal vein pressure further increased. When CCL4 was injected for 8 weeks, the surface and cut surface of the liver were macroscopically visible with diffuse yellow-brown nodules. The hepatic tissue showed widely distributed false lobules, surrounded by thickened and proliferated fibrous septa. In addition to the severe damage of the normal hepatic structure, the hepatocytes in the false lobules were arranged disorderly, and a large number of inflammatory cells were infiltrated. At this time, the portal vein pressure of the rats in the modeling group all exceeded 10 mmHg, and the rats developed ascites.

[0076] Figure 11 It was shown that the level of sC5b-9 in the portal vein of rats in each group increased with the modeling time; when CCL4 was injected for 4 weeks, although the sMAC (soluble membrane attack complex) in the portal vein of some rats increased, there was no difference from the control group as a whole; the deposition of MAC (membrane attack complex) in the portal vein could be observed in the liver of rats, and at this time MAC was only deposited inside the portal vein. When CCL4 was injected for 6 weeks, the sC5b-9 in the portal vein of rats had increased compared with the control group; at this time, more obvious deposition of C5b-9 in the portal vein was observed in the liver of rats. By the 8th week, the sC5b-9 in the portal vein further increased to 690.83 ± 29.6 ng / ml, and a large amount and wide deposition of sC5b-9 were observed in the liver tissue of the rats in the modeling group. At this time, sC5b-9 was not only limited to the portal vein, but also appeared in the lymphatic vessels, fibrous tissues and even hepatocytes around the portal vein.

[0077] 2. Through the above research, 8 weeks was finally selected as the CCL4 modeling node. After 8 weeks of CCL4 modeling, intraperitoneal injection was stopped, and 18 successfully modeled SD rats were randomly divided into 2 groups: CCL4 drug withdrawal group (C1-INH-Stoped) (n = 6) and intervention group (n = 12). Rats in the intervention group were injected with C1-INH via the tail vein 3 times a week for 2 weeks. It was divided into 2 different treatment dose groups: C1-INH 100U low-dose group (C1-INH-Low) (n = 6) and C1-INH 400U high-dose group (C1-INH-Hight) (n = 6)( Figure 12 ).

[0078] The results showed( Figure 13 ), in the C1-INH-Low group, the sC5b-9 in the portal vein of rats decreased to 539.38 ± 58.15 ng / ml (vs 616.61 ± 48.52), and the portal vein pressure (PP) decreased to 8.31 ± 0.58 mmHg (vs 10.49 ± 0.35); in the C1-INH-High group, the sC5b-9 in the portal vein of rats decreased to 470.60 ± 33.67 ng / ml, and the portal vein pressure (PP) decreased to 8.00 ± 1.19 mmHg; there were no significant differences in the arterial pressure and heart rate of rats in the intervention group compared with the drug withdrawal control group.

[0079] The portal vein sC5b-9 and PP of all rats (n = 36) in the natural disease course modeling group and the treatment group were analyzed for correlation to explore the relationship between these two indicators, and it was found that the portal vein sC5b-9 and PP were closely correlated (r = 0.421, P < 0.0001)( Figure 14 ).

[0080] To verify the improvement of complement inhibitors on the oxidative stress of rat liver sinusoidal endothelial cells in vivo, ROS detection was performed on rat liver tissues, and it was found that after 2 weeks of C1-INH treatment, the ROS fluorescence intensity of rat LSECs decreased significantly, that is, the production of ROS decreased( Figure 15 ).

[0081] Example 4 Window Pores on the Surface of Liver Sinusoidal Endothelial Cells

[0082] Complement activation products C3a, C5a, and sMAC were respectively added to heat-inactivated healthy human peripheral serum, and LSEC was treated respectively, and the window pores were observed by scanning electron microscopy. It was found that both C5a and MAC could induce defenestration of LSEC - the window pores on the cell surface became fewer and the pore diameter decreased, which is the main marker of LSEC capillaryization( Figure 16 ).

[0083] The LSECs from 3 different patients were treated with (and without) the addition of the classical pathway inhibitor C1inh to the PVS, and the fenestrae were observed by scanning electron microscopy. The results showed that the de-fenestration of LSECs was significantly reversed ( Figure 17 ).

[0084] In summary, the present invention for the first time discovers that complement inhibitors can improve LSEC dysfunction and reduce portal pressure in cirrhosis without affecting the circulatory pressure by inhibiting complement activation in the portal vein.

[0085] The foregoing description of the disclosed embodiments enables those skilled in the art to practice or use the present invention. Various modifications to the above-described embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.< / pvs>

Claims

1. A drug for reducing the production of ROS in hepatic sinusoidal endothelial cells, and / or enhancing the activity of eNOS in hepatic sinusoidal endothelial cells, and / or treating cirrhotic portal hypertension, characterized in that The drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

2. The drug according to claim 1, wherein, The complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

3. Use of a complement inhibitor in the preparation of a drug for reducing the production of reactive oxygen species (ROS) by hepatic sinusoidal endothelial cells, and / or increasing the activity of endothelial nitric oxide synthase (eNOS) in hepatic sinusoidal endothelial cells, and / or treating cirrhotic portal hypertension.

4. The application according to claim 3, wherein The drug contains a complement inhibitor and a pharmaceutically acceptable carrier or excipient.

5. The application according to claim 3, wherein The complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

6. The application according to any one of claims 3 to 5, characterized in that The complement inhibitor can specifically block the complement activation of the classical pathway.

7. A method for preparing a drug for reducing the production of ROS in hepatic sinusoidal endothelial cells, and / or enhancing the activity of eNOS in hepatic sinusoidal endothelial cells, and / or treating cirrhotic portal hypertension, characterized in that, The method includes preparing the drug with the complement inhibitor as the active ingredient.

8. The method according to claim 7, wherein The drug further contains a pharmaceutically acceptable carrier or excipient.

9. The method according to claim 7, wherein The complement inhibitor can specifically block the complement activation of the classical pathway, and / or the complement activation of the lectin pathway, and / or specifically block the complement activation of the alternative pathway, and / or nonspecifically block the complement activation of the terminal pathway.

10. The method according to any one of claims 7 to 9, characterized in that, The complement inhibitor can specifically block the complement activation of the classical pathway.

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