Dynamics of Sept4 expression in fibrotic livers of mice infected with Schistosoma japonicum.

n order to investigate the dynamics of Septin4 (Sept4) expression and its function in the formation of fibrotic livers in mice infected with Schistosoma japonicum, we constructed the mouse model of S. japonicum egg-induced liver fibrosis for 24 weeks. Immunohistochemical staining, qRT-PCR and Western blot were used to detect the expression of Sept4 and α-smooth muscle actin (α-SMA). We found Sept4 localized in the perisinusoidal space where hepatic stellate cells (HSCs) distribute in the periphery of circumoval granulomas and the portal venule. The expression of Sept4 and α-SMA had a similar significant tendency of an up-regulation to a peak at 12 weeks post-infection (p.i.) followed by a down-regulation. At 24 weeks p.i. both were at a low level. These results suggest that Sept4 and α-SMA may interact together in HSCs. Based on this evidence, we hypothesize that Sept4 seems to be involved in the formation of inflammatory granulomata and subsequent liver fibrosis by regulating HSCs activation.

Manson's schistosomiasis in the undernourished mouse: some recent findings.

This paper deals with current knowledge of the interrelationships between Schistosoma infection and malnutrition. It emphasizes the relevance of these investigations in the face of dynamic and evolving changes occurring in population diets and changes in the epidemiological patterns of schistosomiasis in endemic countries. The paper further discusses the basis for continuing the studies on this subject and the reasons why it represents a misunderstood association. This review also focuses on the cellular and humoral immune responses in the undernourished mouse model infected with Schistosoma mansoni, with updated information on the immune response in wild-type and iNOS knockout mice concerning soluble egg antigen specific antibodies and kinetics of IFN-gamma, IL-4, IL-10 and IL-13 cytokines, in the chronic phase of Manson's schistosomiasis. There is indication that schistosome-infected undernourished mice are able to develop a humoral immune response, but antibody titres are much lower than in the control animals. Cytokine production (IFN-gamma, IL-4, IL-10) is lower in the undernourished mice, but as infection progresses to the chronic phase its kinetics run an antagonistic course when compared to that of well-nourished animals. Marked variation in the secretion of IL-13 (a fibrogenic cytokine) could explain why undernourished mice do not develop liver "pipe-stem" fibrosis described in previous papers on well-nourished animals.

Therapy with bone marrow cells reduces liver alterations in mice chronically infected by Schistosoma mansoni.

AIM: To investigate the potential of bone marrow mononuclear cells (BM-MCs) in the regeneration of hepatic lesions induced by Schistosoma mansoni (S.mansoni) chronic infection. METHODS: Female mice chronically infected with S.mansoni were treated with BM-MCs obtained from male green fluorescent protein (GFP) transgenic mice by intravenous or intralobular injections. Control mice received injections of saline in similar conditions. Enzyme-linked immunosorbent assay (ELISA) assay for transforming growth factor-beta (TGF-beta), polymerase chain reaction (PCR) for GFP DNA, immunofluorescence and morphometric studies were performed. RESULTS: Transplanted GFP(+) cells migrated to granuloma areas and reduced the percentage of liver fibrosis. The presence of donor-derived cells was confirmed by fluorescence in situ hybridization (FISH) analysis for detection of cells bearing Y chromosome and by PCR analysis for detection of GFP DNA. The levels of TGF-beta, a cytokine associated with fibrosis deposition, in liver fragments of mice submitted to therapy were reduced. The number of oval cells in liver sections of S.mansoni-infected mice increased 3-4 fold after transplantation. A partial recovery in albumin expression, which is decreased upon infection with S.mansoni, was found in livers of infected mice after cellular therapy. CONCLUSION: In conclusion, transplanted BMCs migrate to and reduce the damage of chronic fibrotic liver lesions caused by S.mansoni.

Role of partial hepatectomy on Capillaria hepatica-induced hepatic fibrosis in rats.

It is known that hepatic fibrosis may regress following partial hepatectomy, since the hepatic parenchyma regenerates very rapidly, but not the excess of fibrous tissue. The present study evaluated this hypothesis by observing the behavior of systematized septal fibrosis induced by either 30 or 90-day-old Capillaria hepatica infection, in rats subjected to partial hepatectomy. The results revealed that the morphology of the fibrosis was unaffected, but its relative quantity within the microscope field appeared significantly decreased, as a consequence of the increased liver tissue mass following regeneration.

Corilagin Counteracts IL-13Rα1 Signaling Pathway in Macrophages to Mitigate Schistosome Egg-Induced Hepatic Fibrosis.

The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-ß was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-ß compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.

A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis.

The disease manifestations of schistosomiasis arise from the mammalian host-mediated type 2 T-helper cell-induced (Th2) fibro-granulomatous inflammatory response to eggs trapped within host tissues. Activated hepatic stellate cells are well described as the effector cells of hepatic fibrosis in a variety of human diseases and rodent models. The aim of this study was to further understand the mechanism of fibrosis and the role of hepatic stellate cells in hepatic schistosomiasis progression. Groups of female CBA mice, which produce an intermediate degree of Schistosoma japonicum-induced liver fibrosis, were infected with S. japonicum, perfused at fortnightly time points and the liver tissue and contained egg granulomas examined by immunohistochemistry and cytokine and chemokine analysis using quantitative PCR. Immunohistochemistry demonstrated the presence of activated hepatic stellate cells in the periphery of egg granulomas, adjacent to fibrotic areas. Time course analysis demonstrated that the transcription of smooth muscle actin-alpha type 1 collagen, IL-4, IL-13, IL-13Ralpha2 and tissue inhibitor of metalloproteinase-1 mirrored the initial increase and subsequent down-modulation of granuloma diameter in mice. However, the transcription of monocyte chemo-attractant protein-1, Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES), TNF-alpha, IFN-gamma and matrix metalloproteinase-9 paralleled the evolution of the total liver disease burden. Transforming growth factor-beta1 transcription did not appear to be of biological significance in this mouse model. Immunohistochemical analysis of human hepatic granulomas showed close association of smooth muscle actin-alpha-expressing cells with fibrosis in five available cases of end-stage (advanced) schistosomiasis japonica. We conclude that activated hepatic stellate cells play a contributory role in the granulomatous, fibrotic process induced by S. japonicum eggs, both in the murine model and in human disease.

Pathogenesis of septal fibrosis of the liver. (An experimental study with a new model.).

Septal fibrosis is an important, frequent, and non-specific type of fibrosis associated with chronic liver diseases, but its pathogenesis is still poorly understood. An interesting model of septal fibrosis occurs in rats infected with the nematode Capillaria hepatica. This model was used to investigate the pathogenesis, site of origin, structure, and cell-types of septal fibrosis. Forty young adult Wistar rats were inoculated with 800 embryonated eggs of C. hepatica. Daily liver samples were obtained from the 20th to the 39th day after inoculation to cover the critical period when septal fibrosis usually starts. Routine histology, electron microscopy, immunohistochemistry, and indirect immunofluorescence were applied to the study of liver sections. Septal blood vessels were demonstrated by India ink perfusion of the portal vein system. Prominent angiogenesis was observed to precede collagen deposition. Besides angiogenesis and mesenchymal-cell mobilization, septal fibrosis was seen to originate from portal spaces and to course through acinar zone I in between sinusoids, inducing no alterations in them, with no evident participation of stellate hepatic cells. Septal fibrosis appeared as an adaptative type of response of the liver to chronic injury, which resulted in a new structure that is normal to other species and creates accessory vessels that drain portal blood into hepatic sinusoids.

[Regression of hepatic fibrosis]. / Regressão da fibrose hepática.

Extensive and persistent hepatic fibrosis has for a long time been considered irreversible. However, recent studies on the behavior of hepatic fibrosis, especially those related to evolution and involution of advanced schistosomiasis in man, have challenged this concept, and nowadays it is becoming clear that any type of fibrosis is reversible, including that associated with hepatic cirrhosis. The problem consists in identifying and eliminating its cause. Although fibrosis in the liver has little functional significance by itself, its severity derives from associated vascular changes. However, new data on fibrosis regression indicate that disappearance of fibrosis is usually accompanied by remodeling of vascular changes. But, there are peculiarities related to the anatomic type of fibrosis and to its functional significance, which suggest that sometimes fibrosis may indeed be irreversible. These aspects, some of which in need of further studies, are presented and discussed herein.

Dynamic observation of liver fibrosis in mice infected with Schistosoma japonica.

The expression of TNF-alpha in the liver at different periods post Schistosoma japonica infection and the effect on liver fibrosis after supplementary injection of these cytokines were investigated. The mice infected with schistosome cercariae were divided into 3 groups: normal control group, TNF-alpha-untreated infection group and TNF-alpha-treated infection group. ABC immunohistochemistry and pathologic image multimedia quantification system were applied to dynamically detect the activity of TNF-alpha. The results showed that the levels of TNF-alpha in the liver in TNF-alpha-untreated infection group were slowly decreased with prolongation of infection time (from 8th, 11th, 14th to 18th week), while in the TNF-alpha-treated infection group, those were increased significantly after intraperitoneal injection of TNF-alpha at 6th week after infection. At first to 8th week after the final injection of TNF-alpha, the intrahepatic TNF-alpha levels in the TNF-alpha-treated infection group were significantly higher than in the other two groups (P < 0.01), and the granulomatous inflammation and fibrosis in the liver were also milder in the normal control group. It was concluded that at the early stage of Schistosoma japonica infection mouse liver mainly released Th1 cytokine and TNF-alpha from Th1 activated macrophages. Six weeks after infection (post egg deposition), exogenous supplement with intraperitoneal injection of TNF-alpha could induce the enhanced expression of Th1 cytokines and alleviate the liver granulomatous inflammation and fibrosis.

Persistence of hepatic fibrosis and tissue eggs following treatment of Schistosoma japonicum infected mice.

The persistence of hepatic fibrosis and of Schistosoma japonicum eggs in the tissues of mice was examined after chemotherapy. C57BL/6 mice infected with a Philippine strain of S. japonicum were treated with praziquantel or amoscanate 7 or 8 weeks after infection. Groups of mice were killed at the time of treatment and 3, 8, 26, and 52 weeks later. The number of eggs per worm pair in the tissues did not change during the year after treatment. However, S. japonicum eggs injected into the tail vein were gradually destroyed in the lungs. Hepatic fibrosis increased in the 1st few weeks after treatment and did not change significantly thereafter. Praziquantel, but not amoscanate, had an immediate toxic effect on the most mature eggs in the tissues which was accompanied by a marked but transient decrease in eggs passed in the feces. Less mature eggs appeared unaffected by the drug and the passage of eggs in the feces resumed as these matured. Egg passage then ceased as the supply of viable eggs was exhausted.

Immunological basis of septal fibrosis of the liver in Capillaria hepatica-infected rats.

Rats infected with the helminth Capillaria hepatica regularly develop septal fibrosis of the liver similar to that induced by repeated ip injections of pig serum. Fibrosis starts when the focal parasitic lesions begin to show signs of resorption, thus suggesting an immunologically mediated pathogenesis of this fibrosis. To explore this possibility, the development of C. hepatica-related hepatic fibrosis was observed in rats exposed to worm antigens from the first neonatal day onward. Wistar rats (150 g) were either injected ip with an extract of C. hepatica eggs (protein concentration: 1 mg/ml) or received immature eggs by gavage from the first neonatal day until adult life and were then infected with 500 embryonated eggs. Changes were monitored on the basis of serum levels of anti-worm antibodies and hepatic histopathology. Rats submitted to immunological oral tolerance markedly suppressed C. hepatica-related serum antibodies and septal fibrosis of the liver when infected with the helminth later on. Tolerance trials with ip injections of worm antigens gave essentially negative results. The partial suppression of septal fibrosis of the liver after the induction of immunological tolerance to C. hepatica antigens in rats indicates an immunological basis for the fibrosis and emphasizes the importance of immunological factors in the pathogenesis of hepatic fibrosis.

Proteoglycans and glycosaminoglycans synthesized by the hepatic granulomas isolated from schistosome-infected mice and by a granuloma-derived connective tissue cell line.

1. This paper summarizes our studies on proteoglycans and glycosaminoglycans in the hepatic fibrosis occurring in schistosomiasis. 2. We have compared proteoglycans and glycosaminoglycans isolated from schistosomal fibrotic granulomas with those obtained from the cellular and extracellular compartments of a murine cell line derived from schistosome-induced granulomas, the primary cell line "GR". 3. Our results have shown some biochemical and structural similarities between proteoglycans and glycosaminoglycans extracted from granulomas and those synthesized and secreted by GR cells, suggesting that these cells may be the major cell population involved in synthesis and accumulation of these molecules in the schistosomal periovular granulomas in liver. Furthermore, we have shown that GR cells can function as an extramedullary myelopoietic stroma that mediates a long-term myeloid proliferation through an autocrine mechanism where the interaction between myelopoietic growth factors and cell-surface heparan sulfate proteoglycans was characterized.

Colchicine reduces hepatic fibrosis in mice infected with Schistosoma japonicum.

OBJECTIVE: Colchicine has been used clinically to treat hepatic cirrhosis caused by multiple etiologies. MATERIALS AND METHODS: The effect of colchicine on the liver fibrosis of mice infected with Schistosoma japonicum were studied. The morphological observation and morphometric analysis of the infected and untreated, and infected and treated groups were proceeded under the light microscopy, and morphological observation was made under electron microscopy. RESULTS: The results of morphometriic analysis in histological sections showed that the collagen fibers area per schistosome's egg was decreased in the infected and treated groups 10 to 13 weeks after infection. The decrease in the group of 13 weeks was significant statistically. The egg numerical density on area increased continuously from 10 to 13 weeks in both untreated and treated groups in similar degree. The ultrastructural study showed the accumulation of collagen fibrils around the hepatocytes and in the space of Disse decrease and ultrastructural lesion of hepatocytes get recovery in the treated group. CONCLUSIONS: These findings suggest that colchicine has therapeutic effect on schistosomal liver fibrosis, through not only killing off the schistosome but interfering the metabolism of collagen.

Capillaria hepatica-induced hepatic fibrosis in rats: paradoxical effect of repeated infections.

Multiple exposures to parasitic agents are considered an important factor in the genesis of the most severe forms of the diseases they cause. Capillaria hepatica-induced septal fibrosis of the liver in rats usually runs without signs of portal hypertension or hepatic failure. After determining the hepatic profile of 15 animals during the course of a single infection, we submitted 20 rats to multiple Capillaria hepatica infections to determine whether repeated exposures would augment fibrosis production, transforming septal hepatic fibrosis into a true cirrhosis. Ten single-infection rats served as controls. A total of 5 exposures, with 45-day intervals, were made. Histological changes were followed by means of surgical liver biopsies, collected prior to infection and to each re-infection. Functional changes were minimal and transient. Although a slight recrudescence of fibrosis was observed after the first two re-infections and when the single-infected control group was re-infected at the end of the experiment, subsequent re-infections failed to increase the amount of fibrosis. On the contrary, there occurred quantitative and qualitative evidence of collagen degradation and suppression of parasite development. These paradoxical results are in keeping with the hypothesis that a complex immunological modulation participates in the mechanism of hepatic fibrosis induced by Capillaria hepatica infection in rats.

Covalent cross-linking of liver collagen by pyridinoline increases in the course of experimental alveolar echinococcosis.

We report that covalent cross-linking of collagen molecules by pyridinoline increases significantly in liver in a murine model of alveolar echinococcosis. The highest amount of pyridinoline per collagen molecule (up to 3.5 fold the control values) is found in liver parasitic lesions. It is also increased, but to a far lesser extent, at distance from the fibrotic areas, in macroscopically normal zones of the liver, suggesting that the increase in mature collagen cross-linking occurring in the fibrogenesis due to Echinococcus multilocularis infection involves the whole liver. The comparison of these data with those we have obtained in another parasitic disease, murine schistosomiasis leading to a milder liver fibrosis, largely reversible following chemotherapy, supports a relationship between the liver pyridinoline level and the severity of liver fibrosis. Pyridinoline could be a tissular marker of chronic liver fibrosis in parasitic diseases.

[Dynamic changes in hepatic myofibroblast of rabbits with Schistosoma japonicum].

OBJECTIVE: To observe the dynamic changes in hepatic myofibroblasts during the formation of schistosomal hepatic fibrosis and to investigate the pathogenesis of hepatic fibrosis. METHODS: Each rabbit was infected with 80 +/- 1 S japonicum. Liver biopsies were done at different time point after infection and the samples were embedded with paraffin and stained with HE and picric acid-sirius red. The dynamic changes in the areas of granuloma were observed, and the extent of liver fibrosis and the expression of alpha-SMA positive cells were semiquantitated. At the 16th week after infection, the rabbits with S. japonicum were received IFN-gamma after treatment of praziquantel and contrasted with the saline group. RESULTS: The granuloma appeared at the 6th week after infection and its areas reached the biggest at the 8th week. Then the granuloma shrinked gradually, but the extent of liver fibrosis aggravated progressively. The alpha-SMA positive cells were observed at the 4th week after infection and their number enhanced gradually. The extent of liver and the expression of alpha-SMA positive cells were significantly different between each treated group, and the IFN-gamma treated group showed the best result. CONCLUSION: The myofibroblasts play an essential role in the formation and development of schistosomal hepatic fibrosis.

[Ultrastructural dynamic observation on murine schistosomal hepatic fibrosis].

OBJECTIVE: To explore possible mechanisms of hepatic fibrosis by investigating the ultrastructural dynamic changes of liver tissue, especially several kinds of cells related to hepatic fibrosis. METHODS: Murine schistosomal hepatic fibrosis model was established by infecting mice with Schistosoma japonicum cercariae. Routine transmission electron microscopy was used to observe the liver tissue. H.E. staining was used for examining the pathological changes. RESULTS: H.E. staining showed that the model was established successfully. Ultrastructural observation showed that at the 6th week after infection, the necrosis of hepatocytes around the acute granulomas occurred; the number of sinusoidal endothelial fenestrae and vitamin A droplets in fat-storing cells decreased; large phagosomes and rough endoplasmic reticulum could be seen in the cytoplasm of Kupffer's cells. At the 8th week, steatosis was found in some hepatocytes, some microvilli emerged on a few inter-hepatocytic surfaces and the inter-hepatocytic spaces were enlarged. Large collagen fibrillar bundles filled in the perisinusoidal spaces, and capillarization of hepatic sinusoids was observed. Secretory vesicles filled with collagen fibrils appeared in the cytoplasm of fat-storing cells with large amount of collagenous fiber bundles surround the cells. Rough endoplasmic reticulum increased in Kupffer's cells. At the 10th week, fat-storing cells were activated and transformed into myofibroblasts. At the 12th week, the number of myofibroblasts decreased but that of fibroblasts and fiber cells increased. CONCLUSION: Activation of fat-storing cells and transformation from fat-storing cells into myofibroblasts are the critical link in the development of hepatic fibrogenesis following schistosome infection. Kupffer's cells, necrotic hepatocytes and sinusoidal endothelial cells may relate to the activation of fat-storing cells. Capillarization of hepatic sinusoids possibly accelerates the development of hepatic fibrosis.

[Effect of pentoxifylline on the expression of hepatic TGF-beta 1, type I and type III collagen in mice with liver fibrosis due to Schistosoma japonicum infection].

OBJECTIVE: To study the effect of pentoxifylline (PTX) on the content of hepatic TGF-beta 1, type I and type III collagen in schistosome-infected mice with liver fibrosis. METHODS: Forty mice with schistosomiasis were divided into four groups: one group as control without any treatment, other three were treated with praziquantel 500 mg/(kg.d) for 2 d, high dose PTX 360 mg/(kg.d) for 8 wk, and low dose PTX 180 mg/(kg.d) for 8 wk respectively. Immunohistochemical technique and multimedia color pathographic analysis system were applied to observe the content of hepatic TGF-beta 1, type I and type III collagen in mice infected with S. japonicum before and after treatment. RESULTS: The effect of PTX on the content of hepatic TGF-beta 1, type I and type III collagen in mice was related to the dosage of PTX. High dose PTX treatment significantly reduced the content of TGF-beta 1, type I and type III collagen compared to the control (P < 0.01), whereas no difference was found between the group of low dose PTX treatment and control (P > 0.05). CONCLUSION: High dose PTX treatment could reduce the content of hepatic TGF-beta 1, type I and type III collagen significantly in schistosome-infected mice with liver fibrosis.

[Expression of IL-2 and TNF-alpha in the liver and the effect of injection of these cytokines on liver fibrosis in mice infected with Schistosoma japonicum].

OBJECTIVE: To detect the expression of IL-2 and TNF-alpha in the liver at different period postinfection of Schistosoma japonicum and their effect on liver fibrosis after supplementary injection of these cytokines. METHODS: Mice were infected with schistosome cercariae and divided into 3 groups. Two groups were injected (i.p.) every other day with IL-2 and TNF-alpha respectively for consecutive 4 wk. The third group and an uninfected group of normal mice were regarded as control. The ABC immunohistochemistry and pathologic image multimedia quantification system were applied to detect activity of IL-2 and TNF-alpha. RESULTS: The level of IL-2 and TNF-alpha in the liver in infected but untreated group slowly decreased (from 8, 11, 14 to 18 wk). The supplementary injection of the cytokines at 6 wk postinfection in the two groups increased the cytokines significantly, the level of IL-2 or TNF-alpha was higher at 1-8 wk after the last injection than that of both infected and uninfected control groups (P < 0.01). The granulomatous inflammation and fibrosis in the livers of the two groups were slighter than that of the control. CONCLUSION: At the 6th wk postinfection with egg deposition, exogenous supplementation with TNF-alpha or IL-2 induces enhanced expression of the two kinds of cytokines, corresponding to a diminished degree of the liver granulomatous inflammation and fibrosis.

[Influence of interferon gamma treatment on expression of TGF-beta1 and its receptors in liver fibrosis of mice with schistosomiasis japonica].

OBJECTIVE: To investigate the effect of interferon-gamma (IFN-gamma) on the expression of TGF-beta1 and its two membrane receptors--TGF-beta receptor I (TbetaRI), TGF-beta receptor II (TbetaRII), and observe the expression of TGF-beta1, TbetaRI and TbetaRII during the development of liver fibrosis in BALB/c mice infected by Schistosoma japonicum. METHODS: BALB/c mice, aged 6-8 weeks, were infected with cercariae of S. japonicum. The infected mice were divided randomly into three groups 16 week after infection: model group, praziquantel group and praziquantel combined with IFN-gamma group. Liver specimen were obtained at 8, 12, 16 week and at the end of treatment. Pathological examination, immunohistochemistry and RT-PCR were used to evaluate the pathological change, the expression of TGF-beta1, TbetaRI and TbetaRII and the mRNA level respectively. RESULTS: The expression of TGF-beta1, TbetaRI, and TbetaRII can be detected in infected mice, while the expression around egg granulomas enhanced along with the progress of the disease. With the therapy of IFN-gamma, the reduction of egg granulomas, and of the expression of TGF-beta1, TbetaRI and TbetaRII was observed. From the transcription level, it was found that TGF-beta1 mRNA increased at 12 week and peaked at model group, then decreased to the normal level after treatment with IFN-gamma combined with praziquantel. The level of TbetaRII mRNA reduced at 8 and 16 week and returned to normal at the end of treatment. More interestingly, TbetaRI mRNA remained at the normal level on the whole course both in the development of fibrogenesis and the period of treatment. CONCLUSION: The up regulation of TGF-beta1 and down regulation of TbetaRII mRNA may induce liver fibrogenesis and IFN-gamma might suppress TGF-beta1 to reverse fibrosis. The mechanism of the suppression is mediated by down regulation of expression of its two receptors at protein level but not by influencing the mRNA expression.