LuckCong's Health Blog

Hepatic fibrosis of the liver is the excessive deposition of connective tissue fibers, is the proliferation of fiber and fiber uneven decomposition. Fibrosis is the injury to the body's response to a repair, due to a variety of causes of recurrent or persistent chronic liver inflammation, necrosis of the liver can result in the continued proliferation of fiber and the formation of hepatic fibrosis, chronic liver disease in many, especially the chronic The clinical and pathological viral evolution, liver fibrosis and cirrhosis is a continuous process of development, difficult to completely separate the two. 【Treatment】 Anti-fibrosis treatment aimed at reducing the degree of fibrosis, delaying its development, and even reverse the pathological process. To this end anti-fibrosis treatment should include: ① agents for the treatment of the primary disease. If the anti-viral hepatitis, schistosomiasis treatment, prevention and treatment of alcoholism, and so on; ② against the development of liver fibrosis treatment; ③ if he has to the development of liver cirrhosis, it would take to prevent and treat its complications; ④ restoration of liver function and symptomatic treatment. A variety of causes of liver fibrosis is the development of liver cirrhosis on the basis of a common pathology, in recent years, with the mechanism of liver fibrosis in-depth knowledge, in particular, the ECM synthesis and degradation of the in-depth understanding of the molecular biology, many of the studies envisaged in the ECM metabolism, in particular, collagen synthesis and degradation of the areas to take treatment measures, which will now be the main points below. First, inhibition of collagen synthesis 1. Interferon γ-interferon can inhibit fat-storing cell activation, proliferation and reducing α-Actin, Ⅰ, Ⅳ collagen and fibronectin mRNA of the steady-state level of foreign clinical application of low-dose reported minor side effects, the treatment of liver fibrosis may be Effective. α-interferon has antiviral and make tissues in patients with chronic hepatitis C Ⅰ collagen mRNA and TGF-βmRNA lower, to reduce liver fibrosis, but on the other hand, γ-interferon can start macrophages Generate IL-1, TNF-α, the latter two can stimulate the fat-storing cell proliferation and DNA synthesis. It may not be conducive to liver fibrosis. The net effect of these two effects, requires further observation. 2. ACTH Experiment to see it in cell culture and in whole animals inhibited Ⅰ collagen mRNA expression, so that the liver cells and fibroblasts with collagen Ⅰ mRNA level will be reduced, thus inhibiting the synthesis of collagen. But the long-term side effects of more general application, for the very few anti-liver fibrosis treatment. The treatment of chronic autoimmune hepatitis, although can be caused by clinical remission, but it does not prevent the formation of fibrosis. 3. Prostaglandin analogue Prostate known as a wide range of biological activity. Known in the absence of choline in rats ,16,16-Dimethy1 Prostanglandin E2 (DEMG) to reduce fat deposition and fibrosis, the mechanism may be inhibiting the liver Ⅰ collagen mRNA expression. And the work that it can increase the cAMPR cells thereby increasing the degradation of cells. At the same time, the liver can increase blood flow to change the membrane fluidity, changes in blood insulin and glucagon. Inhibiting the release of macrophage inflammatory factor. At present, but not yet for human liver fibrosis. 4. Retinoid-type substances (Retinoids) Such drug-trans retinoic acid (Trans-retinoic Acid) and the order-trans retinoic acid (B-cis-retinoic Acid), to reduce Ⅰ collagen synthesis and its mRNA, to reduce the secretion of monocyte collagenase, but It is a result of Ito cell contents, so there is an increase Ⅰ or type Ⅲ collagen may not necessarily suitable for the treatment of liver fibrosis. 5. Procollagen peptide Procollagen peptide known to both ends of the (non-spherical extension of the Department) can be special-by-cut, the cut-down, such as ammonia-based peptide (that is, P Ⅲ P) feedback can be inhibited collagen synthesis. In a formal application before the need to conduct a detailed study of molecular biology, is currently free to use it related to the treatment of the report. Second, the role of collagen in the pre-mRNA translation after the link 1. Colchicine (Colchicine) The drug in clinical trials at home and abroad. Experimental study tips: Colchicine is anti-tubulin drugs inhibit tubulin polymerization and thus interfere with the cells secrete collagen. It can also stimulate the activity of collagenase and enhance degradation, but also in the role of macrophages, monocytes factor inhibition, inhibition of the release of growth factors to reduce interleukin-Ⅰ secretion. Kershenobich and Rojkind colchicine for the treatment of liver cirrhosis, and so do many years of observation. They adopted a randomized, double-blind, placebo-controlled. In the 14 years follow-up observation of 100 patients with cirrhosis (54 cases of alcohol, 41 cases of hepatitis, 14 cases for other reasons). Observation results show that the median survival time for the group for 11 years, 3.5 years for the placebo group (P = 0.0006). 10-year cumulative survival rates were 56% and 20% (P = 0.0006). The treatment of 30 patients had a liver biopsy in a row, with 9 cases of organized school improvement in the placebo group and 14 cases of liver biopsy done in a row, with 1 case of a turn for the better (P = 0.002), this study tips on colchicine Have a role to extend survival. However, a number of other clinical studies could not confirm these results, as has been (1987,1988) with colchicine treatment of primary biliary sclerosis gradually, to see not prevent liver fibrosis. Wang YC (1994) have used double-blind, randomized controlled methods of treatment of 100 cases of hepatitis B liver cirrhosis, compared with the control group, regardless of changes in liver histology, the serum fibrosis, as well as the development of the disease, such as mortality, colchicine No group effect. It appears in the anti-fibrosis of the goods on the treatment of little hope. 2. Proline -4 - hydroxylase inhibitor Experiments to prove that it can inhibit the hydroxylation of proline, hydroxyproline the formation reduction, thus reducing the procollagen three α-helical chain stability. The two had a joint venture of-Pyridine, Pyridine 2,4-dicarboxylate (2,4-PDCA) and Pyridine2 ,5-dicarboxylate, in animal experiments have the effect of hepatic fibrosis, but the side effects in clinical trials have been suspended. 3. Metal ions agent Two-pyridine (αα'-dipyridy1) can be complex and inhibit iron Proline hydroxylase activity, so that a new synthesis of collagen peptide chain as a result of α-hydroxylation can not be inhibited the formation of three spiral in the cells were released; Recently, it also found that lower-Ⅰ collagen mRNA stability so that to reduce the synthesis of collagen. Its anti-fibrosis yet to be confirmed by further studies. Green-D-amine copper ion agent, and the copper ion is Lai-amine oxidase important cofactor, so this drug can inhibit the activity of the enzyme so that new collagen secretion by not cross-linked with each other; it Wilson's disease have a better effect, but due to other causes of human and animal liver fibrosis had no significant effect, and long-term side effects more. 4. Proline analogues (Proline Analogs) Such compounds are small acridine acid (Azetidine Carboxylicacid), Shun -4 - hydroxy proline, and so on, it can be replaced by proline and collagen in combination to form a spiral of non-collagen. This easy for the collagen protein hydrolysis, resulting in the formation of extracellular matrix reduction. At present, only the rats in the experiment to see made to reduce the effects of collagen. Its greater toxicity, but also in the trial who have not yet. 5. Procollagen to collagen into the inhibitor The basic role in order to prevent the cut off both ends of the procollagen peptide molecules, resulting in the formation of collagen molecules can not, and so that the damage to the stability of collagen, is the first trial of arginine and its analogs (Convanine), yet for animal experiments And the treatment of the human body. 6. Lathyrus-(Lathyrogen) One containing β-aminopropionitrile and amino acetonitrile, which inhibits lysyl oxidase activity to prevent the collagen fibers of the bridge link, liver fibrosis is currently limited to experimental studies have not yet used in human liver fibrosis. Third, to promote the degradation of collagen treatment At present, the promotion of collagenase activity of drug research is only in its infancy. However, this type of drug clinical significance, because the promotion of excessive deposition of collagen degradation may have to reverse the formation of hepatic fibrosis. Lieber CS, and other reports unsaturated lecithin (PUL) to reduce the baboons of alcoholic cirrhosis, further in vitro by cell culture-based study found that it Ⅰ procollagen mRNA expression had no effect, but can of fat-storing cell collagenase Increased activity doubled. This prompted the promotion of degradation activity may be the treatment of baboons PUL-alcoholic liver fibrosis in rats. The ongoing multi-center clinical trial. Fourth, gene therapy Wu CH, and other reports, with antisense oligonucleotide (ASO) DNA, in order to offer more lysine salivary mucin (AsORPL) as the carrier, the leading role in the 3-T-AsGR cells, to see ASOE and ASOC were able to inhibit Ⅰ procollagen mRNA 73% and 67%. The work of the anti-gene therapy for liver fibers break open the prospect. It appears from the above, although the metabolism of collagen in the treatment of all aspects of the experimental study, but the establishment of an effective and less side-effects of drug treatment need to be a long-term efforts. Fifth, Chinese medicine treatment Since the founding of New China, the motherland of medical applications in the treatment of chronic liver disease has made significant progress, and anti-fibrosis or cirrhosis treatment of the experimental and clinical research: the liver and soft Tom Kennedy (by wan, South Korea, 1979), cucurbitacin B, Qi Oleanolic acid (five Han, 1979,1981), and glycyrrhizin glycyrrhetinic acid (Zhao Qi Deng, 1983), drugs such as salvia (such as the Ling Wang Zhen, 1982), Cordyceps sinensis, Salvia (science Ma Hui, and so on, 1988) , And peach kernel Cordyceps sinensis (Wang Yurun, Liu Ping, Liu, 1985,1991), on March 7 Tian (Xiao Cheng, 1988), Danshen mixture (such as Wang, 1990), the internal organs of blood Zhu Yu Tang (Wu Song, Li Bai, 1991) , Liver and Culture Complex granules (such as Yang Zhengyun, 1990), kidney Yijing, Qi Yin, Qingrejiedu Ogata (such as Fanzong Pang, 1991), Cordyceps sinensis (such as Li-huang, 1992), soft liver granules (Li-fu, 1992 ). Research shows that in recent years: the pathology of mild chronic hepatitis in 62.6 percent have liver fibrosis, moderate, severe chronic hepatitis and cirrhosis are 100% liver fibrosis, which Chinese medicine treatment of liver fibrosis, chronic hepatitis and liver from Hardening of the dialectical approach as a whole so as to the basis of pathogenesis, the development of reason and law, parties, drugs. In the medical literature of the motherland with chronic hepatitis and cirrhosis of the name, but included in the "jaundice", "Xie Tong," and "congestion" and "disorder product" and "expansion swollen," all evidence of disease. Modern Chinese medicine research that chronic hepatitis and cirrhosis due to the early heat of evil outstanding, lingering in the course of time, causing injuries to internal organs and blood. Evil FU as a result of blood loss and sub-righteousness Gan Qi Qi, stagnation of blood stasis. No righteousness, coupled with phlegm cement Qi blood stasis syndrome were led to the plot. Both liver disease for a long time, the spleen by Fan Wei, the missing movements Division, declining air and increase the blood deficiency Qi. And then kidney disease for a long time, resulting in kidney-yin deficiency of liver or spleen Yang Deficiency. As a result of liver, spleen, kidneys are damaged, gas, blood, water pump knot. Some experts have pointed out that Chinese medicine: To summarize the pathogenesis of the central link: Qi stagnation of blood to the liver of this, Shi Du evil Heat missed two standard blood, liver without raising blood loss and soft, non-renal clearance and fill in missing run. Qi will have to rule by promoting blood circulation, nourishing Rougan-based, and nourishing the liver and spleen and kidney warming or, if more than evil outstanding, backed up Quxie. Based on the above-mentioned, in recent years, chronic hepatitis and cirrhosis of the early Chinese medicine treatment of promoting blood circulation to more than Relieving Blood-based rules, and to Bu Xu Qi, nourishing the liver and kidney tonic or Rougan. Ma Xue Hui, Han by the family of five, and other experimental research on animals shows that Salvia experimental acute liver damage liver cells reduce the degeneration and necrosis of lower alanine aminotransferase, and lipid-lowering increase in liver glycogen. Partial hepatectomy on the animal can promote liver regeneration. Of experimental liver fibrosis can prevent the occurrence of liver cirrhosis and liver collagen to promote the role of the re-absorption, see also on the experimental acute liver failure have a role in prevention and treatment. The mechanism is likely to reduce the time endotoxemia, and enhance the function of Kupffer cells; to prevent the production of free radicals, reducing lipid peroxidation; stability of the liver cell membrane and the cell membrane; increase in liver enzymes to prevent the drug flow, such as Ca. In the experimental liver fibrosis and cirrhosis observed Salvia can reduce serum levels of hyaluronic acid to reduce the collagen content in the liver of animals and Fn, Ln generation. Wang Yurun, Liu Ping, Liu used, such as peach kernel extracts of Cordyceps sinensis combined treatment of schistosomiasis liver fibrosis, P Ⅲ P, blood, urine hydroxyproline, liver, such as collagenase, as observed, the results showed that the pathogen (that is, Schistosoma) after the treatment, the treatment of liver fibrosis in patients with liver metabolism of collagen break down a certain role. Wang role in this chapter, such as promoting blood circulation to Salvia-based medicine Relieving Blood on the experimental compound to observe the treatment of liver fibrosis. See traditional Chinese medicine for blood circulation CCL4 toxic injury albumin, as well as damage the immune liver fibrosis have effect, the drug can be applied to varying degrees, to reduce the development of liver fibrosis, can already form a clear reversal of liver fibrosis were . Histopathological observation indicates that promoting blood circulation Relieving Blood compound can inhibit the connective tissue fibers in Ⅰ, Ⅲ, Ⅴ-proliferation and collagen deposition, to stop along the inter-lobular and lobular to the extension of the period. At the same time, laboratory research has also observed that the compound Relieving Blood promoting blood circulation, whether preventive or therapeutic drug treatment have improved liver fibrosis in rat liver tissue and serum collagenase activity, and improve the liver Collagenase activity in the organization and the potential of collagenase activity ratio. Note the degradation of the increased activity of traditional Chinese medicine for promoting blood circulation Relieving Blood anti-fibrosis mechanisms is another important aspect. As for this part of the role of Chinese herbal compound, molecular biology, which can inhibit liver Ⅱ, Ⅲ collagen mRNA expression, can inhibit the in vitro cultivation of the fat-storing cell Ⅳ collagen mRNA expression. That the role of traditional Chinese medicine is part of the collagen gene transcription level. In patients with chronic hepatitis and cirrhosis of clinical application, but also better results. In the treatment or alleviate the symptoms disappear, to narrow the spleen, portal vein diameter widened to alleviate. GOT increased to 73% back to normal. Serum P Ⅲ P, Ln by the increased concentration dropped back to normal. Tip of the side of anti-fibrosis is a valid prescription. In addition to promoting blood circulation Relieving Blood rule, there are other laws and effective treatment of experimental studies, such as kidney Yi Jing, Qi and Yin Qingrejiedu such as the law of traditional Chinese medicine for liver fibrosis in rats have varying degrees of treatment. It seems a great deal of work from home, Chinese medicine treatment of liver fibrosis have great potential, should take it seriously. 【Etiology】 The mechanism of liver fibrosis Fat-storing cell of the liver to produce a variety of extracellular matrix of the main sources. In the occurrence of liver fibrosis and in the development of fat-storing cell activation into myofibroblast-like cells (Myofibrblast-like cells) and fibroblasts (Fibroblast), and thus fat-storing cell activation process has become a mechanism of liver fibrosis One of the focuses of research. Ito adjustment factors can be divided into two types soluble and insoluble, the former for a variety of extracellular matrix, which includes a variety of growth factors, cytokines. Under normal liver sinusoidal endothelial function of the basement membrane (Ⅳ collagen and laminin) for the maintenance of fat-storing cell of the rest (storage Vit. A, secretion of collagen Ⅳ) play an important role, was once the basement membrane Damage to the fat-storing cell phenotype can be changed. Ito regulation of cell growth factor and a lot of factors. To promote the proliferation of PDGF, EGF, IGF-1, FGF-2, TGF-α; can inhibit the proliferation of alcohol and retinol and retinoic acid ET; TGF-β itself on the fat-storing cell growth inhibition However, by stimulating PDGF, and FGF-2 expression can promote their growth. In these cytokines in TGF-β1 and PDGF in a more in-depth study. In the liver TGF-β1 from the major fat-storing cell, Kupffer cells, endothelial cells, platelets and liver cells, through other paracrine regulation of cells. TGF-β1 can promote fat-storing cell expressed and secreted Ⅰ, Ⅲ, Ⅳ collagen, fibronectin, cell-adhesion, cartilage FN, adhesion-thrombosis, Biglycan and Decrin. But also through the promotion of the role of autocrine TGF-β1 expression of its own, its metal matrix protein (collagenase, Stromelysin-) and plasminogen activator inhibit the expression, but also the promotion of endothelial cells and fat storage Expression of cell plasminogen activator inhibitor (PAI-1) and tissue inhibitor of metalloproteinase (TIMP). Therefore, TGF-β1 is found that the most important fibrosis induced by cytokines. PDGF may be a variety of cells. Is a very strong induced mitogen through α and β-receptor on the fat-storing cell proliferation and promote the role and TGF-β1 could enhance the role; itself on the extracellular matrix of expression had no effect. TNF-γ produced by the cell, it's fat-storing cell activation, growth and inhibit the secretion of collagen. ET-1 in the liver by cell sinusoidal endothelial activation and the resulting fat-storing cell. Ito a high level of expression of ET-1 receptor, through paracrine and autocrine role of the cause of the fat-storing cell activation and contraction of collagen fibers, leading to sinus blood flow and change the structure of the Gan Xiaoye distorted. Fat-storing cell to activate the three-stage study leave. First, before the inflammatory phase (Preinflammatory Phase) When the substance of liver damage, increased permeability of cell membranes, releasing "hormones injury" (Wound Hormone), through paracrine role of the fat-storing cell activation. In vitro experiments showed that rat liver cells may promote the release of fat-storing cell proliferation of cytokines - Ito cells, liver cells and activated factor (Hepitoin, Hepatocellular Ito Cell Initiator). At the same time, the liver of interstitial sinusoidal injury undermined if the endothelial function under the basement membrane, but also for the fat-storing cell's phenotype changes in its activation. Second, the inflammatory phase (Inflammatory Phase) As the substance of liver injury, Kupffer cells, monocytes and macrophages, lymphocytes, platelet activation and release of a variety of media and inflammatory cytokines, such as acute phase proteins (IL-1, IL-6, TNF-α) And TGF-1, EGF, PDGF, TGF-α, TGF-β, and so on. These factors also through paracrine way to promote the fat-storing cell proliferation and fibrosis. This phase of the Kupffer cells secreted by fat-storing cell of a cytokine-induced and expressed the PDGF receptor, PDGF react to muscle activation and proliferation of fibroblast-like cells. TGF-β can not only increase the PDGF on the fat-storing cell proliferation, but also to promote its range of expression and secretion of extracellular matrix and inhibit the degradation. Third, after the inflammation stage (Postinflammatory Phase) In the above two stages by the paracrine way to activate the expression of fat-storing cell of a large number of TGF-α, TGF-β, FGF and its receptor, through autocrine role in fueling the proliferation of their own and a large number of synthesis and secretion of collagen and other Kind of extracellular matrix. At the same time can also activate the role of paracrine other is still in the "static" state of the fat-storing cell. Even if this mechanism can explain the primary catalyst to lift, liver fibrosis can still continue the process of development. In each of these stages in the role of matrix-degrading enzyme can be summarized as follows: fat-storing cell secretion of type Ⅳ collagenase destruction of the normal sinusoidal endothelial function under the basement membrane, and promote their proliferation and activation; TGF-β inhibition interstitial glue The original enzyme activity to stimulate TIMP activity and thus promote the deposition of extracellular matrix.