For more than 40 years, Chinese medical anti-fibrosis studies have shown that fibrosis can be reversed. Clinically in China, anti-fibrosis with Chinese medicine is the hot field of research in the treatment of chronic liver diseases. With the development of the knowledge of molecular biology of the fibrosis, and integration of Chinese and Western medicine, MCM has developed effective anti-fibrosis treatments. With these treatments, it is possible to reverse or slow down the progress of the fibrosis and restore normal liver structure.

1. Anti-Fibrosis Treatments Developed Based on TCM Theories: In China, most TCM anti-fibrosis studies were done in chronic hepatitis B and schistosomiasis. In TCM's theories, the main pathogenesis of liver fibrosis is termed as "blood stasis" and the main treatment principle for it is called " huo xue hua yu" and its English translation is "blood activating and stasis expelling". The interpretation of this treatment principle is to improve the liquidity of the blood, to reduce its viscosity, to reduce the clustering of red blood cells and platelets, and to promote the phagocytosis of the macrophage, to promote microcirculation, and removal of circulatory immune complex. In our protocols, we use Circulation P formulas as one of the major anti-fibrosis remedies. Circulation P formula is an alternation of a traditional formula called "Xue Fu Zhu Yu Tang." Chinese studies found that taking "Xue Fu Zhu Yu Tang" formula for three months, patients' fibrosis markers, such as HA (hyaluronic acid), LN (Laminin), CIV (collagen IV), PCIII (procollagen type III) levels reduce significantly (p<0.05). Our Circulation P Capsule is composed based on the Xue Fu Zhu Yu Tang and plus some more potent active ingredients, such as notoginsenoside, chuanxingzine, tanshinone, and ferulic acid, mentioned in the later section. Circulation P Capsule is main remedy we use for anti-fibrosis through "blood activating and stasis expelling" mechanism.

2. Anti-Fibrosis Treatments Developed Based on MCM (Integrative TCM and Western Medicine): The studies on MCM anti-fibrosis treatments were focused on how to suppress the activities of HSC and the cytokines and reduce the accumulation of ECM. Restore the equilibrium of production and deposition of ECM. This is the key to reverse the fibrosis. Fibroblastic activity is a dynamic process and theoretically it is reversible. An effective anti-fibrosis treatment should suppress the ECM synthesis and promote degradation of the ECM. Chinese herbal treatment can affect both sides. It can suppress the synthesis and secretion of ECM and promoting its decomposition.

Because fibrosis involves many factors, anti-fibrosis therapy is a multi-frontal treatment. There are five important approaches to hold or reverse fibrosis and early cirrhosis:

A. Prevent liver cell injury and anti-inflammation treatments: The liver cell injury sets out the liver fibrosis process. So treating the primary liver disease, such as chronic viral hepatitis to reduce the inflammation and protecting the liver cell damage is the most important anti-fibrosis therapy. For chronic liver diseases caused by other causes, such as alcoholic liver disease and parasitic liver disease, stop drinking and eliminate the parasite is the key to hold the progression of fibrosis. Healing the inflammation can reduce the releasing of cytokines, such as PDGF, TGF-ß etc. and in turn, it can decrease the activities of HSC therefore, it suppresses the liver fibrosis. MCM has developed many herbal remedies for controlling liver inflammation, such as schizandrin B and C, glycyrrhizin, oleanolic acid, silymarin, oxymatrine, and Sedum.

Most of these herbal remedies can lower the ALT and AST level, protect the intact of the liver cell membrane and reduce the inflammatory cell infiltration and liver cell necrosis. These herbal active ingredients have been tested in animal models, such as the liver CCl4 intoxication models and extensively used in clinical treatments of chronic liver diseases in China for many years. But only controlling the primary disease is not enough, once HSC being activated, even without the effects of inflammation, it can still continue synthesis of ECM and fibrosis will continue. So anti-fibrosis treatments aiming at other pathogenesis are needed.

B. Suppressing activities of HSC and related cytokines and promoting HSC apoptosis. HSC is the major source of fibroblastic activities and suppress its activity is an important anti-fibrosis treatment. Histochemisry of liver biopsy showed that the activities of HSC greatly increased during the chronic liver inflammation. After the Chinese herbal treatment the number of HSC reduced markedly. A pure HSC string culture showed that with herbal intervention, its replication reduced greatly. The treatment also suppressed the expression of collagen I, III, V type mRNA, TGF-ß mRNA, and TIMP mRNA. At same time, found the Kupffer cells, T-lymph cells decreased. It showed that the treatment suppressed the inflammation and in turn suppressed the HSC proliferation. MCM formula 861* has a promoting effect on HSC apoptosis showing both on in vitro culture and clinical in vivo studies. After Formula 861 treatment the number of activated HSC were decreased and the apoptosis of HSC could be seen in the liver biopsy. Another anti-fibrosis formula investigated the main sera-pharmacological mechanism of Tidu Hugan Formula* (TDHGF) medicated serum on fibrotic activities and found it could obviously inhibit the proliferation of HSC. TDHGF medicated serum could obviously inhibit the yield of cytokine TGF-b1 and hence inhibit the liver fibrosis. The active ingredients of Salvia miltiorrhiza, iH764-3** has been shown strong effects on promoting HSC apoptosis. This herb and its active ingredients have been main ingredients of many of our formulas for chronic liver disorders. TGF-b1 is one of the strongest cytokines in the fibrosis promoting factors. MCM studies found that Formula 861, salviolic acid B**, and oxymatrine can suppress HSC and Kupffer cells secret TGF-b1.

C. Suppressing the synthesis and secretion of ECM. In order to monitor the progress of the fibrosis and to evaluate of the efficacy of the anti-fibrotic treatment, following serum markers, HA (hyaluronic acid), LN (Laminin), CIV, PCIII (pre-collagen type III), have been frequently used to show the changes in ECM. TDHGF* medicated serum could obviously inhibit the production of collagens. Ginkgolides has the effects of inhibiting platelet-activating factor (PAF) thus helps to reduce the level of fibrosis related serum makers, such as HA, CIV, PCIII and LN. Salviolic acid B** has been shown suppressive effects on the secretion of TGF-b1 by HSC and also inhibit its collagen synthesis. Animal cirrhosis model treated with Chinese herbal Formula 861* shown organic changes:

1. The color and texture of the liver surface obviously improved compare with control group.

2. The three-dimensional fiber structure of cirrhotic liver showed honeycomb structure. After formula 861 treatment, this honeycomb structure disappeared.

3. Measured by quantity of hydroxyproline (represents the collagens in the liver tissue) found that after herbal treatment, total collagen, and type I, III, and V collagen obviously reduced.

4. The mRNA detected by a cDNA probing obviously reduced and the same reduction of type I, III, and V collagen mRNA, TGF-ß mRNA after herbal treatment. This showed that herbal treatment affected the gene translation level.

D. Promoting decomposition of ECM. Normally, fibroblastic and fibrocatalytic activities exist side by side. In the early stage of fibrosis, the catalytic enzyme MMP(Matrix metalloproteinases) also increase, but less than the increase of fibrosis. Advanced to late stage, MMP activities decrease and cause fiber catalytic activities decline. This causes the net increase of the ECM. The treatment of formula 861 and Fuzhen Huayu Capsule can increase the quantity and activities of MMP. After MCM herbal treatment, HSC expresses more MMPmRNA, the activities of MMP in supernate of HSC culture increase. This showed that Chinese herbal treatments strengthened the MMP gene expression and activities, thus strengthened the catalytic activities of collagen. TIMP (element metal protease inhibitor) can suppress the activities of MMP. During fibrosis, the production of TIMP increases. After the treatment of formula 861 and Fuzhen Huayu Capsule, TIMPmRNA in the liver tissue and HSC cultures decrease dramatically. This is obviously beneficial the reverse of fibrosis.

E. Prevent Liver Sinusoid Capillarization
The liver sinusoid capillarization causes the loss of endothelial fenestrations, which is a very important pathological change during liver fibrosis. It blocks the chemical substances exchange between the liver cells and the blood circulation. Increase the resistance of blood flow and causes the hypertension of portal vein. The Cordyceps sinensis and Fuzheng Huayu Capsule have been showed that they can reverse the capillarization process and prevent the fenestration and improve the material exchange between the liver cells and the blood circulation.

Anti-Fibrosis Herbs and Their Active Ingredients:

Based on clinical and experimental research works, we have found following Chinese herbs to have anti-fibrosis effects: Salviae Miltiorrhziae Radix, Cordyceps sinensis, Persicae Semen, Notoginseng Sanchis Radix, Stephania tetrandra Radix, Cnidii Rhizoma, Angelicae Radix, and Astragali Radix.

Some herbal formulas have been studied and have shown effective anti-fibrosis actions: Xue Fu Zu Yu Tang, Jiang Gan Shun Jian Tang, Fuzheng Huayu Capsule, and 861 Fomula.

Recent studies on the active ingredients of herbal anti-fibrosis remedies have found many effective compounds. Some of these active anti-fibrosis ingredients are listed in following:

1. Cordyceps sinensis (Cs), observed in rat CCl4 fibrostic model, the Cs treated group have a lighter inflammation, fatty degeneration and less liver cell damage. From the observation of ALT, HA, LN in liver tissue, found Cs has strong effects on improving regeneration of hepatocytes and suppression of fibroblasts and collagen fibers. This substance is the ingredient of our Cordyceps Capsule.

2. Glycyrrhizin, an active ingredient of Glycyrrhiza uralensis Fisch (Licorice root). It can reduce the level of ALT, AST, fatty deposit (steatosis), and fibrosis. Shown in rats models, it can obviously suppress type I and III pro-collagen synthesis. Reduce the over active fibrosis-related cytokines in the liver cell. It has definite liver cell protective effects. This substance is the ingredient of our Glycyrrhizin Capsule.

3. Danshensuan A, is a water soluble ingredient of Salvia miltiorrhiza Bge. It has excellent anti-oxidant effects. Animal experiments found that it has obvious effects to suppress the proliferation of fibroblastic cells and the synthesis of intracellular collagen. This substance is one of the main ingredients of our Circulation No.1 and Circulation P Capsule.

4. Extract IH764-3 of Salvia miltiorrhiza, It can obviously reduce the fibrosis in rat fibrostic models. Obviously reduce the content of hydrooxyproline (Hyp), type I and III collagen, and HA, LN. Improve the liver function, and improve the liver histology. This substance is one of the main ingredients of our Circulation No.1 and Circulation P Capsule.

5. Chuanxionyzine, its chemical name is Pyrazine. It is an active ingredient of Ligusticum chuanziong Hort. In rat CCl4 fibrostic model, it can reduce ALT, HA, type III pro-collagen, and obviously reduce the fibrosis. It is also an anti-oxidant and can increase SOD activities and reduce the level of MDA (methylenedioxyamphetamine). This substance is one of the main ingredients of our Circulation No.1 and Circulation P formulas.

6. Oxymatrine, it is the extract of Sophorae Subprostratae Radix. It has anti-viral, anti-inflammatory, and immune regulatory effects. Recent studies found, it has obvious anti-fibrosis effects. An obvious fibrosis suppressive effect shown at a concentration of 62.5 ng/ml. It suppresses the fibroblastic cell activities and expression of mRNA of type III pro-collagen. The potency of these effects is dose-dependent. Clinical studies found that the treated group have lower levels of ALT, CIV, HA, and TNF-b, and less inflammatory activities and fibrosis than that of the control group. This substance is one of the main ingredients of our Hepa F. #2 and #1a Capsules.

7. Extracts of Persicae Semen, Studies done at Shanghai TCM University found that it can promote the action of collagen enzyme, reduce type III pre-collagen and increase the metabolite of collagen, hydroxyproline level in the blood. This substance has been successfully used to treat cirrhosis caused by viral hepatitis and parasitic hepatitis. It is one of major ingredients of Circulation No.1 and Circulation P formulas.

8. Taurine, it is an active ingredient of nature calculus Bovis. In TCM, the gallstone of Bos Taurus demesticus, used to remove heat from the heart, induce resuscitation, eliminate phlegm, relieve convulsion and remove heat and toxic substance. Recent studies found that it can suppress HA and the expression of mRNA of type I and III Pro-collagens. It can also increase the content of cAMP in the plasma of the cells. In rats fibrotic model made by continuous injection of bovine albumin, found that treated with this substance, the collagen deposit in the liver tissue greatly reduced and the content of Hyp in the liver obviously reduced. In rat CCl4 fibrotic model, it can obviously reduce the contents of Hyp, type I and III pro-collagen, HA, LN and improve the liver function and improve the liver histology.

9. Fustin, an active ingredient of Gleditsia sinensis Lam. It can obviously suppress the activities of PDGF (platelet delivered growth factor) and TGF-b1. PDGF induces the proliferation of the HSC and promote the activities of TGF-b, which increases collagen and EMC synthesis. This substance suppresses PDGF, so it can suppress fibrosis in two phases.

10. Tetrandrine is an active ingredient of Stephania tetrandra S. Moore. This substance can affect the Ca channel and its distribution in the cells. It has also anti-inflammatory, anti-allergic, analgesic, and anti-bacteria effects. It can suppress the collagen and DNA synthesis in the HSC. The suppression is dose dependent. After treated with this substance, the serum HA, P-II-P, and the collagen deposit decrease obviously. At the same time the inflammation, cell necrosis, and inflammatory cell infiltration reduces. This substance has been used in treating lung fibrosis and got very good clinical outcome.