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Biomedical subjects

M Sata

Publications and source records attributed to M Sata.

At least 73 records · Page 4Linked to original sources
PubMed2000

Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.

BACKGROUND: Short-term histologic improvement in hepatitis C-related hepatic fibrosis has been noted in studies with more than 2 years of follow-up, but the long-term effects of interferon therapy on hepatic fibrosis remain unclear. OBJECTIVE: To assess changes in hepatic fibrosis after interferon therapy in patients with chronic hepatitis C. DESIGN: Retrospective cohort study. SETTING: 7 university hospitals and 1 national hospital in Japan. PATIENTS: 593 patients with chronic hepatitis C who underwent a paired liver biopsy from 1987 to 1997. Of these, 487 patients received interferon therapy and 106 patients were untreated. INTERVENTION: Patients in the treatment group received a 2- to 6-month course of interferon within 6 months after the initial biopsy. MEASUREMENTS: Fibrosis and inflammatory activity in paired biopsy samples obtained a median of 3.7 years apart (range, 1 to 10 years) were graded by using the criteria of Desmet and colleagues (F0 to F4) and those of the French METAVIR Cooperative Study Group (A0 to A3), respectively. Changes in fibrosis staging and activity scores and yearly rates of fibrosis progression and regression were calculated. RESULTS: 183 of the 487 interferon-treated patients showed a sustained virologic response. Activity grade was unchanged in most of the untreated patients and improved in 89% (CI, 83% to 93%) of patients with a sustained virologic response. A sustained response to interferon was associated with a mean (+/-SE) reduction in fibrosis score of -0.60+/-0.07 at less than 3 years of follow-up and -0.88+/-0.08 at 3 years or more of follow-up. The rate of fibrosis progression was -0.28+/-0.03 unit/y (regression) in patients with sustained response, 0.02+/-0.02 unit/y in patients with nonsustained response (P< 0.001), and 0.10+/-0.02 unit/y in untreated patients. CONCLUSION: Although the time between biopsies partly affected the patient's clinical course, the differences observed here suggest that in patients with chronic hepatitis C, regression of fibrosis is associated with sustained virologic response to interferon therapy.

Adult↗
PubMed2000

Effect of interferon treatment on serum 2',5'-oligoadenylate synthetase levels in hepatitis C-infected patients.

Interferon (IFN) is widely used for patients with hepatitis C. Less than half of treated patients respond to IFN therapy, however, and increased resistance to IFN is particularly observed in genotype 1b patients. Recently, genotype 1b patients with the wild type sequence in the NS5A gene were shown to be resistant to therapy, suggesting that the NS5A protein may be involved to IFN resistance. Thus, we investigated the serum 2',5'-oligoadenylate synthetase (2',5'-OAS) levels before and during IFN treatment. In addition, other biochemical markers and NS5A mutations were also examined in 30 HCV genotype 1b-positive patients. Before IFN treatment, 2',5'-OAS activity in sera was significantly lower in wild type patients than in mutant type patients. All patients were subsequently enrolled in IFN therapy, and 2',5'-OAS activity was elevated both in wild and mutant type patients, irrespective of the number of mutations in NS5A. Logistic regression analysis revealed that clearance of serum HCV RNA was independently related to the pretreatment viral load and NS5A mutations, but not to serum 2',5'-OAS activity. We concluded that the NS5A protein, that is associated with the outcome of IFN therapy, affects the kinetics of IFN-induced molecules, such as 2', 5'-OAS. 2',5'-OAS activity does not, however, seem to be related to long-term virological response to IFN therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed2000

Empty virus-like particle-based enzyme-linked immunosorbent assay for antibodies to hepatitis E virus.

Hepatitis E, an enterically transmitted non-A, non-B hepatitis, is a serious viral infection that occasionally causes large epidemics in developing countries. In developed countries, the disease only appears sporadically due to the transmission routes, and it is considered to be less important. The hepatitis E virus (HEV) cannot grow in cultured cells and no reliable assay system has ever been developed. In addition, the present diagnostic are not perfect, and actual rates of HEV infection may be underestimated. Highly purified empty virus-like particles (VLPs) of HEV have been produced by the use of a recombinant baculovirus vector in insect cells. Using these VLPs as an antigen, an enzyme-linked immunosorbent assay (ELISA) for antibodies to HEV was developed. A panel of 164 sera that were randomized and coded, and sera collected periodically from three patients with hepatitis E were used for the evaluation. The sensitivity of the assay was shown to be equal to or better than that obtained in previous research that used the same serum panel. The ELISA demonstrated that the serum IgM level of the patients was highest at the onset of the clinical illness and then rapidly decreased. In contrast, a high level of circulating IgG antibody titers lasted for more than 4 years. In Japan, a non-endemic country, the prevalence of the IgG class antibody to HEV in healthy individuals was found to range from 1.9% to 14.1%, depending on the geographical area. Only one out of 900 (0.1%) serum samples was IgM-positive. The IgM class antibody to HEV was detected in 10.8% of non-A, non-B, and non-C acute hepatitis patients in northeast China, whereas none of the patients in Korea had the IgM antibody. The ELISA utilizing the VLPs is sensitive and specific in its detection of the IgM and IgG antibodies to HEV. The ELISA is therefore useful for diagnosing HEV infection and for seroepidemiological study of hepatitis E.

Adolescent↗
PubMed2000

Fas ligand-deficient mice display enhanced leukocyte infiltration and intima hyperplasia in flow-restricted vessels.

Fas ligand (FasL) is a death factor that induces apoptosis in Fas-bearing cells. To explore the role of FasL in vascular lesion formation, we analysed leukocyte infiltration and lesion formation in a flow-restriction model of vascular injury that results in neointima formation in the presence of intact endothelium. The left common carotid arteries of wild-type and FasL-deficient (gld) mice were ligated just proximal to the carotid bifurcation. Three days after the ligation, T lymphocyte and macrophage infiltration into the common carotid artery was notably enhanced in the gld mice relative to the wild-type C57BL/6J mice. Four weeks after the ligation, the common carotid arteries developed neointima-like lesions consisting primarily of alpha -smooth muscle actin-positive cells beneath an endothelial cell monolayer. Neointima formation was greater in the gld mice than in wild-type mice. These data provide mouse genetic evidence suggesting that Fas-mediated cell death can function to restrict inflammation and intimal hyperplasia during vascular remodelling.

Actins↗
PubMed2000

A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia.

Genetically modified mice serve as a powerful tool to determine the role of specific molecules in a wide variety of biological phenomena including vascular remodeling. Several models of arterial injury have been proposed to analyze transgenic/knock-out mice, but many questions have been raised about their reproducibility and physiological significance. Here, we report a new mouse model of vascular injury that resembles balloon-angioplasty. A straight spring wire was inserted into the femoral artery via arterioctomy in a small muscular branch. The wire was left in place for one minute to denude and dilate the artery. After the wire was removed, the muscular branch was tied off and the blood flow of the femoral artery was restored. The lumen was enlarged with rapid onset of medial cell apoptosis. While the circumference of the external elastic lamina remained enlarged, the lumen was gradually narrowed by neointimal hyperplasia composed of smooth muscle cells. At 4 weeks, a concentric and homogeneous neointimal lesion was formed reproducibly in the region where the wire had been inserted. Similar exuberant hyperplasia could be induced in all strains examined (C57BL/6J, C3H/HeJ, BALB/c, and 129/SVj). This model may be widely used to study the molecular mechanism of post-angioplasty restenosis at the genetic level.

Angioplasty, Balloon↗
PubMed2000

High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications.

Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-beta2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

Antibodies, Anticardiolipin↗
PubMed2000

Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis.

OBJECTIVE: The balance between apoptosis and cell proliferation is vital for cellular homeostasis, yet little is known about the mechanisms that coordinate these two cell fates, particularly in the vessel wall. It is well established that the members of Bcl-2-gene family are regulators of apoptosis, but their role in cellular proliferation is less clear. METHODS: We analyzed the effects of disrupting Bcl-2 expression in vascular smooth muscle cells (VSMCs) by adenoviral-mediated delivery of a hammerhead ribozyme against bcl-2 mRNA (Ad-Rbz-Bcl-2). RESULTS: Forced ablation of Bcl-2 in balloon-injured rat carotid arteries reduced cell number and inhibited neointimal hyperplasia. In vitro, VSMCs transduced with the Ad-Rbz-Bcl-2 underwent apoptosis as indicated by a reduction in cell number and DNA fragmentation. Ad-Rbz-Bcl-2-transduced cells also exhibited aberrations in both G1- and S-phases of the cell cycle. However, forced perturbations in cell cycle activity by serum-stimulation or treatment with chemical inhibitors did not affect Ad-Rbz-Bcl-2-induced cell death, indicating that these cell cycle changes are not essential for apoptosis. CONCLUSION: These data show that physiological levels of Bcl-2 are essential for VSMC viability and that ablation of Bcl-2 alters cell cycle activity through the execution of the apoptotic process.

Adenoviridae↗
PubMed2000

Role of ATP7B in biliary copper excretion in a human hepatoma cell line and normal rat hepatocytes.

BACKGROUND & AIMS: Wilson's disease is a genetic disorder characterized by the accumulation of copper in the body caused by a defect of biliary copper excretion. The Wilson's disease gene has been cloned; however, the precise localization of the gene product (ATP7B) and its role in biliary copper excretion have not been clarified. METHODS: We constructed a chimeric protein between green fluorescent protein (GFP) and ATP7B (GFP-ATP7B) and expressed it in a human hepatoma cell line (Huh7) and isolated rat hepatocytes. The Golgi apparatus, late endosomes, lysosomes, and bile canaliculus were visualized by fluorescence microscopy. Brefeldin A and nocodazole were used to redistribute the Golgi proteins. Bafilomycin A1 was used to analyze the association between GFP-ATP7B and the late endosomes. RESULTS: GFP-ATP7B colocalized with rhodamine-dextran and late endosome markers but not with the Golgi markers, lysosome markers, or a tight junction protein. Brefeldin A and nocodazole redistributed the Golgi proteins, but they did not affect the distribution of ATP7B. CONCLUSIONS: Although it is widely believed that ATP7B is located at the Golgi apparatus, its main localization is in late endosomes. ATP7B seems to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes.

Adaptor Protein Complex gamma Subunits↗
PubMed2000

High plasma cardiac natriuretic peptides associated with enhanced cyclic guanosine monophosphate production in preascitic cirrhosis.

BACKGROUND/AIMS: The initial abnormalities of renal sodium handling in cirrhosis remain unclear. The aim of this study was to characterize sodium metabolism in preascitic cirrhosis. METHODS: Ten patients with preascitic cirrhosis and ten controls were studied. All subjects ate a diet providing 120 mmol sodium during an equilibration period lasting 5 days and the study day. On the study day, after remaining in bed, plasma levels of atrial natriuretic peptide, brain natriuretic peptide, renin activity, aldosterone, noradrenaline, and cyclic guanosine monophosphate were measured at 7 am. Thereafter, they were instructed to maintain an upright posture until dinner and the measurements were repeated at 9 am and 6 pm. After having dinner, all subjects were asked to remain in bed and the measurements were repeated at 11 pm. To measure renal sodium and cyclic guanosine monophosphate excretion, 24-h urine collections were performed, starting from 7 pm on the day before the experimental day. RESULTS: Plasma levels of atrial natriuretic peptide, brain natriuretic peptide and cyclic guanosine monophosphate in patients with preascitic cirrhosis were significantly elevated compared with those in controls at every sampling time (p=0.03 or less, p= 0.04 or less, and p=0.01 or less). In contrast, plasma renin activities at every sampling time were significantly lower in patients than in controls (p= 0.04 or less). Plasma aldosterone and noradrenaline levels were not significantly different at every sampling time in the two groups. No significant differences in daily renal sodium excretion were found. However, urinary cyclic guanosine monophosphate excretion was significantly higher in patients than in controls (p<0.01). CONCLUSIONS: The initial abnormalities of sodium metabolism in cirrhosis might be characterized by blunted renal responsiveness to natriuretic peptides. The results of the study also provide indirect evidence that the impairment is mainly located at postreceptor levels of signal transduction pathway to the peptides, if the activation of antinatriuretic factors other than renin-angiotensin or sympathoadrenergic systems does not play a role.

Adult↗
PubMed2000

Histopathological and immunohistochemical study of oral lichen planus-associated HCV infection.

Background: In recent years, it has been suggested that oral lichen planus (OLP), a chronic inflammatory keratotic lesion, is related to hepatitis C virus (HCV) infection. Therefore, we evaluated whether the presence or absence of HCV infection caused any histopathological differences in OLP tissues. Methods; The subjects consisted of 31 patients with HCV-related liver disease complicated by OLP (32 OLP lesions) and ten OLP patients without complications due to either HCV infection or liver disease (control). A histopathological evaluation was performed in these patients. In addition, immunostaining was done on nine OLP tissues infected with HCV and on six OLP tissues without HCV infection in order to evaluate lymphocyte subsets (T cells or B cells) infiltrating into topical regions with OLP. Furthermore, the severity of hepatic fibrosis and inflammation was evaluated in liver tissues obtained by liver biopsy from six patients with HCV-related liver disease to evaluate whether there were any relationships between the severity of hepatic fibrosis or inflammation and OLP tissues. Results: There were no significant differences in the histopathological characteristics specific to OLP or in the ratios of T and B cells among infiltrating lymphocytes regardless of the presence or absence of HCV infection. Moreover, there were no certain relationships between the severity of hepatic fibrosis or inflammation and the severity of lymphocytic infiltration in OLP. Conclusions: HCV infection does not appear to influence the histopathological and immunohistochemical features of OLP.

Journal Article↗
PubMed2000

Second generation amplicor-HCV monitor assay: clinical features and predictors of the response to interferon.

The aims of this study were to compare the amplicor-HCV monitor assay versions 1.0 and 2.0, and to investigate the clinical usefulness of this assay in patients with chronic hepatitis C. We retrospectively analyzed 154 patients, and 133 of these patients received interferon therapy. Sixty-nine patients were complete responders (CR), and 64 were non-responders. Serum HCV RNA levels of version 1.0 and version 2.0 and HCV genotypes were determined in all patients. There was a good correlation between versions 1.0 and 2.0 in both genotype 1b and 2a, 2b (r=0.907 and 0.726, respectively). In genotype 1b, the mean HCV RNA level obtained by version 1.0 was 384+/-547 kcopies/ml and that obtained by version 2.0 was 488+/-825 kI.U./ml. In genotype 2a/2b, the mean level obtained by version 1.0 was 170+/-369 kcopies/ml and that obtained by version 2.0 was 340+/-402 kI.U./ml. Discriminant analysis revealed that the discriminating points of IFN response were 168 kcopies/ml (genotype 1b, version 1.0), 106 kcopies/ml (genotype 2a and 2b, version 1.0), 102 kI.U./ml (genotype 1b, version 2.0), and 277 kI.U./ml (genotype 2a and 2b, version 2.0). When the patients were stratified according to the discriminating points, the CR rate below the discriminating points were 73.8 and 86.2% in versions 1.0 and 2.0, respectively, in genotype 1b, and the rates were 73.2 and 82.3% in genotype 2a/2b. In addition, receiver-operating characteristic analysis revealed that version 2.0 had significantly better discriminative ability in patients with genotype 1b. We conclude that the second version of the amplicor-HCV monitor assay measures HCV RNA levels with the same precision as version 1.0 and is more useful for the prediction of interferon response than version 1.0.

Journal Article↗
PubMed2000

Two-year follow-up study after treatment with lamivudine for chronic hepatitis B: seven cases reported.

2 times baseline) and returned to seropositive for HBV DNA and HBeAg after lamivudine cessation. One of these five patients died of liver failure 3 months after treatment. However, in two of five patients whose alanine aminotransferase (ALT) had rebounded, HBV DNA became undetectable, and the ALT levels markedly decreased 2 years after the end of therapy. Since the disappearance of HBV DNA and stabilization of the ALT level were observed within two patients by 2 years after cessation of treatment, the patients whose ALT had rebounded should be followed up for a long-term period. To confirm the effect of lamivudine, long-term follow-up in many patients is necessary.

Journal Article↗
PubMed2000

Ursodeoxycholic acid reduces expression of heat shock proteins in primary biliary cirrhosis.

BACKGROUND: To identify injured cells in the liver of patients with primary biliary cirrhosis (PBC) and to determine the effects of ursodeoxycholic acid (UDCA) on these cells, we examined the cellular expression of heat shock proteins (HSPs) in PBC both before and after treatment with UDCA. METHODS: Expression of HSP70 and ubiquitin in PBC livers (n=34) was evaluated immunohistochemically as well as by immunoblot analysis, and compared with chronic viral hepatitis type C (n= 9), primary sclerosing cholangitis (n=8), and controls (n=7). RESULTS: Immunoblot analysis demonstrated a marked expression of HSP70 and ubiquitin in PBC. Immunohistochemical staining for both HSP70 and ubiquitin was observed to be strong in biliary epithelial cells (BECs) and moderate in both hepatocytes and arteries in PBC. Cellular labelling rates for HSP70 and ubiquitin of bile ducts in PBC were significantly higher (p<0.01) than those in chronic viral hepatitis type C, primary sclerosing cholangitis, or controls. The labelling rates for HSP70 and ubiquitin in bile ducts and in hepatocytes were significantly decreased (p<0.01) after treatment with UDCA in PBC. CONCLUSIONS: The present data suggest that BECs and hepatocytes significantly express HSPs even in the early stages of PBC, and that UDCA treatment significantly improves their condition. The immunohistochemical evaluation of HSPs is a valid and sensitive means to identify injured cells in PBC.

Adult↗
PubMed2000

Detection of hepatitis C virus RNA in oral lichen planus and oral cancer tissues.

Hepatitis C virus (HCV) infection not only causes chronic liver diseases but shows extrahepatic manifestations as oral lichen planus (OLP) and oral cancer. To elucidate the direct relationships among these diseases and HCV infection, we investigated the detection of positive- and negative-strand HCV-RNA from serum, OLP (n=19), and oral cancer (n=17) tissues. We used a sensitive reverse transcription to polymerase chain reaction (RT-PCR) method, and analyzed sequences from the HCV El/E2 region of the genome from serum and tissue. Positive and negative HCV-RNA strands were observed in 13 (92.9%) and 3 (21.4%) OLP tissues, respectively. In oral cancer tissues, positive HCV-RNA strands were detected in all tissues from anti-HCV positive patients. Negative HCV-RNA strands were observed in 5 of 7 (71.4%) patient's tissues. Furthermore, it was confirmed that the sequence from one of each OLP and oral cancer patient differed between serum and tissue HCV-RNA. These results may indicate that HCV persists and replicates in these lesions, suggesting a pathological role for HCV, although the mechanisms are unclear.

Adult↗
PubMed2000

Lamivudine therapy for a hepatitis B surface antigen (HBsAg)-positive leukemia patient receiving myeloablative chemotherapy and autologous stem cell transplantation.

Hepatitis B virus (HBV) can be a cause of fatal liver failure after chemotherapy for viral carrier patients and limits the indication of myeloablative therapy for them. We describe an HBsAg-positive leukemia patient who successfully underwent autologous PBSC transplant. After chemotherapeutic treatment his serum HBV DNA level rose in association with hepatitis. To prevent progression to fulminant hepatitis, we administered lamivudine, a viral reverse transcriptase inhibitor, during the transplantation procedure. The patient did not show any increase of HBV DNA or a worsening of his hepatitis. Thus, lamivudine may be a promising treatment for HBsAg-positive patients receiving myeloablative chemotherapy and autologous stem cell transplantation.

Adult↗
PubMed2000

Cholestasis with altered structure and function of hepatocyte tight junction and decreased expression of canalicular multispecific organic anion transporter in a rat model of colitis.

Cholestasis is frequently associated with inflammatory bowel disease. Because some cholestasis is resulted from altered hepatocyte tight junctions (TJs) or the canalicular multispecific organic anion transporter, we have investigated the following topics in a rat model of inflammatory bowel disease: (1) alterations in hepatocyte TJs and in the canalicular multispecific organic anion transporter, (2) etiologic factors for cholestasis, and (3) effects of antibiotics on cholestasis. Rats with trinitrobenzene sulfonic acid-induced colitis were studied 24 hours after treatment. Hepatocyte TJs and the canalicular multispecific organic anion transporter were evaluated by immunostaining for TJ-associated proteins, 7H6 and ZO-1, and multidrug resistance protein 2 (mrp2). To investigate etiologic factors causing cholestasis, portal endotoxin and proinflammatory cytokines were examined. The effects of polymyxin B, penicillin G, or metronidazole on immunostaining for 7H6, ZO-1, mrp2, and cholestasis were investigated. (1) Immunostaining for 7H6 and ZO-1 colocalized outlining the bile canaliculi and immunostaining for mrp2 localized on the canalicular membrane in controls. Treatment with trinitrobenzene sulfonic acid induced significant cholestasis and caused translocation of immunostaining for 7H6, but not that for ZO-1, to the cytoplasm and diminished immunostaining for mrp2 on the canaliculus membrane. (2) The levels of portal endotoxin, but not proinflammatory cytokines, was increased. (3) Polymyxin B, but not the other antibiotics, prevented alterations in immunostaining for both 7H6 and mrp2, and cholestasis. We described that both hepatocyte TJs and the canalicular multispecific organic anion transporter were altered and that gut-derived endotoxin levels in the portal blood were increased in this rat colitis model.

Animals↗
PubMed2000

Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.

We investigated whether anti-transforming growth factor beta (TGF-beta) molecular intervention can halt the progression of liver fibrosis in rats. To block TGF-beta action in a specific manner, we prepared an adenovirus expressing a truncated type II TGF-beta receptor (AdTbeta-TR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor. We also used an adenovirus expressing bacterial beta-galactosidase (AdLacZ) as a control adenovirus. Rats were treated with dimethylnitrosamine (DMN) for 3 weeks; then, AdTbeta-TR, AdLacZ, or saline was intravenously applied once, followed by an additional 3-week DMN treatment. The ratio between the truncated receptor and the wild-type receptor at the mRNA level was 15 at 1 week and 10 at 3 weeks after gene transfer. Immunohistostaining analysis showed that the truncated receptor was expressed mainly in septal cells including hepatic stellate cells. Liver fibrosis, as assessed by histology, hydroxyproline content, and the serum level of hyaluronic acid, progressed during the additional 3-week DMN treatment. However, in rats infected with AdTbeta-TR, the fibrosis remained at the level seen in rats given DMN for only 3 weeks. All AdTbeta-TR-treated rats remained alive, whereas DMN-treated rats infused with either AdLacZ or saline died of liver dysfunction. In the livers of AdTbeta-TR-treated rats, electron microscopy showed: 1) less accumulation of extracellular matrix proteins in the Disse's spaces; 2) regenerated hepatocytes; and 3) fat droplet-rich "quiescent" hepatic stellate cells. Our results demonstrate that TGF-beta plays a critical role in the progression of liver fibrosis, and suggest that anti-TGF-beta intervention should be therapeutic in already-established fibrotic livers, not only by suppressing fibrosis, but by facilitating hepatocyte regeneration.

Animals↗