Stability of cervical esophagogastrostomy via hand-sewn anastomosis after esophagectomy for esophageal cancer.

The aim of the present study is to evaluate the outcome of hand-sewn esophagogastric anastomosis during radical esophagectomy for esophageal cancer. The outcomes of 467 consecutive esophageal cancer patients who underwent cervical esophagogastric anastomosis using interrupted and double-layered sutures after radical esophagectomy via right thoracotomy or thoracoscopic surgery were retrospectively reviewed. Anastomotic leakage, including conduit necrosis, occurred in 11 of 467 patients (2.4%); 7 of 11 (63.6%) cases experienced only minor leakage, whereas the other four (36.4%) patients had major leakage that required surgical or radiologic intervention, including two patients of conduit necrosis. Anastomotic leakages were more frequently observed after retrosternal reconstruction compared with the posterior mediastinal route (P < 0.0001). The median time to healing of leakage was 40 days (range: 14-97 days). Two patients (2/467, 0.4%) died in the hospital due to sepsis caused by the leakage and conduit necrosis. Twelve patients (2.6%) developed anastomotic stenosis, which was improved by dilatation in all patients. Hand-sewn cervical esophagogastric anastomosis is a stable and highly safe method of radical esophagectomy for esophageal cancer.

A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components.

Genotyping graft livers by short tandem repeats after human living-donor liver transplantation (n = 20) revealed the presence of recipient or chimeric genotype cases in hepatocytes (6 of 17, 35.3%), sinusoidal cells (18 of 18, 100%), cholangiocytes (15 of 17, 88.2%) and cells in the periportal areas (7 of 8, 87.5%), suggesting extrahepatic cell involvement in liver regeneration. Regarding extrahepatic origin, bone marrow mesenchymal stem cells (BM-MSCs) have been suggested to contribute to liver regeneration but compose a heterogeneous population. We focused on a more specific subpopulation (1-2% of BM-MSCs), called multilineage-differentiating stress-enduring (Muse) cells, for their ability to differentiate into liver-lineage cells and repair tissue. We generated a physical partial hepatectomy model in immunodeficient mice and injected green fluorescent protein (GFP)-labeled human BM-MSC Muse cells intravenously (n = 20). Immunohistochemistry, fluorescence in situ hybridization and species-specific polymerase chain reaction revealed that they integrated into regenerating areas and expressed liver progenitor markers during the early phase and then differentiated spontaneously into major liver components, including hepatocytes (≈74.3% of GFP-positive integrated Muse cells), cholangiocytes (≈17.7%), sinusoidal endothelial cells (≈2.0%), and Kupffer cells (≈6.0%). In contrast, the remaining cells in the BM-MSCs were not detected in the liver for up to 4 weeks. These results suggest that Muse cells are the predominant population of BM-MSCs that are capable of replacing major liver components during liver regeneration.

Using sorafenib for recurrent hepatocellular carcinoma after liver transplantation--interactions between calcineurin inhibitor: two case reports.

No effective therapeutic approaches have been available for early recurrences following liver transplantation for hepatocellular carcinoma (HCC). The prognosis for such patients has been poor. We encountered two patients with recurrent HCC following liver transplantation, and in the prescribed sorafenib after the failure of various therapeutic approaches. In vitro experiments have shown sorafenib to be metabolized by the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and glucuronosyltransferase (UGT1A9). The metabolic pathway is predicted to overlap that of calcineurin inhibitors (CNIs). In the two cases in which we used sorafenib, tacrolimus (FK506) was used in case 1 and cyclosporine, in case 2. We therefore have also reported the blood levels of the CNI at the time of sorafenib use. Patients with recurrent HCC following liver transplantation were less tolerant of sorafenib than advanced HCC patients who had not undergone transplantation. Poor tolerance was believed to be due to pharmacological interactions of sorafenib and CNIs. Likewise in our patients, determining blood levels of sorafenib, including the area under the blood concentration-time curve of at least the CNI, in each case allowed us to determine the optimal sorafenib dose for each patient. In the future, when administering sorafenib to treat recurrent liver cancers following liver transplantation, the dose of sorafenib should be started at 200 mg/d and gradually increased while measuring CNI blood levels.

Cerebral microbleeds on MR imaging: comparison between 1.5 and 7T.

BACKGROUND AND PURPOSE: The detection of microbleeds differs strongly between studies, due to differences in scan protocol. This study aims to compare the visualization of microbleeds with 3D T2*-weighted imaging at 1.5T with 3D dual-echo T2*-weighted imaging at 7T. MATERIALS AND METHODS: Thirty-four patients (29 male; mean age, 58 ± 12 years) with atherosclerotic disease from the Second Manifestations of ARTerial Disease study were included. 3D T2*-weighted imaging at 1.5T and dual-echo T2*-weighted imaging at 7T were done in all patients. The presence and number of definite microbleeds were recorded on minimal intensity projections. Inter- and intraobserver reliability was assessed with Cohen κ test and the ICC. The difference in presence and number of microbleeds was tested with the McNemar test and Wilcoxon signed rank test. RESULTS: The interobserver ICC at 7T was 0.61 and the intraobserver ICC was 0.94, whereas at 1.5T the interobserver ICC was 0.50 and the intraobserver ICC was 0.59. Microbleeds were detected in significantly more patients on 7T (50%) than on 1.5T scans (21%) (P = .001). The number of microbleeds was also higher at 7T (median, 0.5; range, 0-5) than on 1.5T (median, 0.0; range, 0-6) (P = .002). CONCLUSIONS: 3D dual-echo T2*-weighted imaging at 7T results in better and more reliable detection of microbleeds compared with 3D T2*-weighted imaging at 1.5T.

Anti-apoptotic function of Xbp1 as an IL-3 signaling molecule in hematopoietic cells.

Cytokine signaling is critical for proliferation, survival and differentiation of hematopoietic cell, and interleukin-3 (IL-3) is required for maintenance of many hematopoietic cell lines, such as BaF3. We have isolated apoptosis-resistant clones of BaF3 using retroviral insertional mutagenesis and the Xbp1 locus was identified as a retroviral integration site. Expression and splicing of the Xbp1 transcript was conserved in the resistant clone but was promptly disappeared on IL-3 withdrawal in parental BaF3. IL-3 stimulation of BaF3 cells enhanced Xbp1 promoter activity and induced phosphorylation of the endoplasmic reticulum stress sensor protein IRE1, resulting in the increase in Xbp1S that activates unfolded protein response. When downstream signaling from IL-3 was blocked by LY294002 and/or dn-Stat5, Xbp1 expression was downregulated and IRE1 phosphorylation was suppressed. Inhibition of IL-3 signaling as well as knockdown of Xbp1-induced apoptosis in BaF3 cells. In contrast, constitutive expression of Xbp1S protected BaF3 from apoptosis during IL-3 depletion. However, cell cycle arrest at the G1 stage was observed in BaF3 and myeloid differentiation was induced in IL-3-dependent 32Dcl3 cells. Expression of apoptosis-, cell cycle- and differentiation-related genes was modulated by Xbp1S expression. These results indicate that the proper transcriptional and splicing regulation of Xbp1 by IL-3 signaling is important in homeostasis of hematopoietic cells.

Cancer imaging: novel concepts in clinical magnetic resonance imaging.

Cancer is a major public health problem in the Western world. Imaging is of crucial importance in oncology, because it may reduce cancer-related morbidity and mortality. To improve tumour evaluation, there is a need for functional imaging modalities that go beyond gross assessment of anatomical abnormalities and allow visualization and quantification of biochemical processes in vivo. Magnetic resonance imaging (MRI) not only provides anatomical information, but also offers a wide range of functional sequences that may aid the evaluation of cancerous lesions. Furthermore, MRI provides the opportunity to guide and monitor anticancer therapies noninvasively. The aim of this review is to highlight some of the most promising developments of MRI in the functional assessment of cancer and the guidance and monitoring of (novel) anticancer therapies.

Lymph node detection by MRI before and after a systematic pelvic lymphadenectomy.

OBJECTIVE: Pelvic lymphadenectomy is considered the gold standard to diagnose and possibly treat lymphatic metastases in gynaecological cancer patients. The aim of this study is to evaluate whether all presurgical MRI detected lymph nodes were removed during the systematic pelvic lymph node dissection (PLND) in cervical cancer patients. METHODS: 21 consecutive cervical cancer patients who were scheduled to undergo a PLND were evaluated by a MRI scan prior to surgery and 6 weeks afterwards. All patients had tumour metastasis negative lymph nodes at histopathological examination. RESULTS: On average, 10 pelvic lymph nodes (range 5-17) per patient were detected by presurgical MRI. Postsurgical MRI scans showed that on average 1 (range 0-3) pelvic node per patient was not removed by surgery. In total, 14% of the presurgical MR detected nodes were not removed by surgery (31/225). Approximately half of all lymph nodes that remained after surgery were located in the obturator region. In spite of the remaining nodes, surgery and histopathological examination did detect more nodes than MRI: on average 21 lymph nodes per patient (range 9-59) were removed. Another 2 lymph nodes (range 0-6 per patient) were judged to be newly developed after surgery. CONCLUSION: Although surgery was able to remove many more lymph nodes than those detected by presurgical MRI, 14% of presurgical MRI detected lymph nodes were not removed by PLND. The value of MRI prior to surgery for the detection of pathological lymph nodes is a subject of further research.

Ten-year experience of totally laparoscopic liver resection in a single institution.

BACKGROUND: Recent developments in liver surgery include the introduction of laparoscopic liver resection. The aim of the present study was to review a single institution's 10-year experience of totally laparoscopic liver resection (TLLR). METHODS: Between May 1997 and April 2008, 82 patients underwent TLLR for hepatocellular carcinoma (HCC) (37 patients), liver metastases (39) and benign liver lesions (six). Operations included 69 laparoscopic wedge resections, 11 laparoscopic left lateral sectionectomies and two thoracoscopic wedge resections. Nine patients underwent simultaneous laparoscopic resection of colorectal primary cancer and synchronous liver metastases. RESULTS: Median operating time was 177 (range 70-430) min and blood loss 64 (range 1-917) ml. Median tumour size and surgical margin were 25 (range 15-85) and 6 (range 0-40) mm respectively. One procedure was converted to a laparoscopically assisted hepatectomy. Three patients developed complications. Median postoperative stay was 9 (range 3-37) days. The overall 5-year survival rate after surgery for HCC and colorectal metastases was 53 and 64 per cent respectively. CONCLUSION: TLLR can be performed safely for a variety of primary and secondary liver tumours, and seems to offer at least short-term benefits in selected patients.

Hyperbaric oxygenation therapy enhances the protective effect of moderate hypothermia against forebrain ischemia in the gerbil hippocampus.

Moderate hypothermia may have a beneficial effect on the neurological outcome. However, ischemic deterioration such as brain swelling during rewarming has been reported as a notable complication after successful therapeutic cerebral hypothermia. In this study, we investigated the effects of hyperbaric oxygenation during rewarming. Forebrain ischemia was produced in 24 gerbils and sham ischemia in 8 animals. Then ischemia-treated animals were divided into 3 groups, whole-body moderate hypothermia (31 degrees C for 60 min) and hyperbaric oxygenation (HBO2) (2- atmosphere absolute for 60 min using 100% oxygen) during rewarming group (n = 8), moderate hypothermia without HBO2 group (n = 8), and sham treatment without hypothermia and without HBO2 group (n = 8). Both the hypothermia group (77.9 +/- 48.1 neurons per mm, mean +/- SD) and hypothermia + HBO2 group (127.6 +/- 29.7 neurons per mm,) showed significant preservation of CA1 pyramidal neurons in the hippocampus compared to that in the sham treatment group (6.4 +/- 2.7) (p < 0.01). Furthermore, the hypothermia + HBO2 group showed significantly greater preservation of CA1 pyramidal neurons than the hypothermia group (p < 0.05). These results suggest that HBO2 during rewarming preserves the protective effect of hypothermia against ischemic neuronal damage.

Hepatocyte growth factor gene therapy accelerates regeneration in cirrhotic mouse livers after hepatectomy.

BACKGROUND: Impaired regeneration and dysfunction of the cirrhotic liver following partial hepatectomy (PHx) are the most serious risk factors for postoperative liver failure. AIMS: Using naked hepatocyte growth factor (HGF) plasmid by the electroporation (EP) in vivo method, we investigated HGF for its role and mechanism of proliferation and restoration of liver mass in cirrhotic mice following PHx. ANIMALS: Eight week old female mice were used. METHODS: HGF plasmid 50 micro g was injected intramuscularly and transferred by EP in vivo once a week for three weeks. After establishment of carbon tetrachloride induced cirrhosis, mice underwent PHx. The HGF treated group was given naked HGF plasmid four days before PHx, and additional HGF was given once a week until they were killed, while a control group was given only empty plasmid. Mice were killed 2, 4, 10, and 14 days after PHx. Morphological and functional restoration of the liver were examined, as well as activation of mitogen activated protein kinase (MAPK) and mRNA levels of HGF activator (HGFA). RESULTS: The HGF treated group demonstrated a continuous threefold increase in HGF levels in plasma. Therapy with HGF in cirrhotic PHx resulted in effective liver regeneration via restoration of HGFA and activation of MAPK p44/p42, accelerated normalisation of liver function, and increased collagen degradation. CONCLUSIONS: HGF gene therapy by in vivo EP may be useful for hepatic resection in cirrhotic livers by stimulating liver proliferative and collagenolytic capacities, as well as accelerating functional recovery.

Attenuated acute liver injury in mice by naked hepatocyte growth factor gene transfer into skeletal muscle with electroporation.

BACKGROUND: Hepatocyte growth factor (HGF) plays an essential role in hepatic development and regeneration, and shows proliferative and antiapoptotic activity in hepatocytes. AIMS: To establish an effective new method for HGF gene transfer in vivo and to investigate its effects in acute experimental liver injury. ANIMALS: Eight week old female mice were used. METHODS: Rat HGF gene in a modified pKSCX plasmid was transferred to the tibialis anterior muscle by electroporation using a pulse generator. Four days later, plasma HGF concentrations were determined by enzyme linked immunosorbent assay every two days for three weeks. To confirm the efficacy of electroporation, a plasmid bearing green fluorescence protein (GFP) was transferred similarly. Four days after electroporation, carbon tetrachloride (CCl(4)) was administered to mice to induce acute liver injury. Plasma alanine aminotransferase (ALT) activity was measured. Hepatic apoptosis was assessed by Hoechst 33258 staining and the TUNEL method. RESULTS: Fluorescence microscopy showed strong green fluorescence where the GFP gene had been transferred into muscle. In mice given the HGF gene, HGF in plasma was increased up to fourfold from pretreatment amounts, peaking 6-9 days after electroporation and quickly decreasing within three weeks. Compared with the group without HGF transfer, the percentage of apoptotic hepatocytes after CCl(4) intoxication was significantly lower, as was ALT activity. In addition, ALT activity normalised more rapidly in the HGF gene transfer group. CONCLUSIONS: Naked DNA injection and transfer by electroporation efficiently brings about HGF expression in vivo, which can attenuate acute liver injury.

Non-contrast enhanced MR venography using 3D fresh blood imaging (FBI): initial experience.

OBJECTIVE: This study examined the efficacy of 3D-fresh blood imaging (FBI) in patients with venous disease in the iliac region to lower extremity. MATERIALS AND METHODS: Fourteen patients with venous disease were examined [8 deep venous thrombosis (DVT) and 6 varix] by 3D-FBI and 2D-TOF MRA. All FBI images and 2D-TOF images were evaluated in terms of visualization of the disease and compared with conventional X-ray venography (CV). RESULTS: The total scan time of 3D-FBI ranged from 3 min 24 sec to 4 min 52 sec. 3D-FBI was positive in all 23 anatomical levels in which DVT was diagnosed by CV (100% sensitivity) as well as 2D-TOF. The delineation of collateral veins was superior or equal to that of 2D-TOF. 3D-FBI allowed depiction of varices in five of six cases; however, in one case, the evaluation was limited because the separation of arteries from veins was difficult. CONCLUSION: The 3D-FBI technique, which allows iliac to peripheral MR venography without contrast medium within a short acquisition time, is considered clinically useful.

Recombination hot spot of hepatitis B virus genome binds to members of the HMG domain protein family and the Y box binding protein family; implication of these proteins in genomic instability.

OBJECTIVE: Previously we hypothesized that the occurrence of hepatocellular carcinoma (HCC) is enhanced by genomic instability induced by the integrated hepatitis B virus (HBV) DNA. Using an in vitro recombination assay, we showed that a subgenomic fragment of HBV DNA designated 15AB (nt1855-1914) is indispensable for in vitro recombination, and also showed the existence of 15AB binding protein. On the assumption that the 15AB binding protein may be a candidate cellular recombinogenic protein which accelerates genomic instability and hepatocarcinogenesis, we tried to isolate it by southwestern screening. RESULTS AND CONCLUSION: We obtained several positive clones including mouse upstream binding factor (UBF) and DNA binding protein A (dbpA). UBF belongs to an HMG domain protein family and dbpA belongs to a Y box binding protein family. 15AB binding seemed to be mediated by the conserved DNA binding domains in these families, because other members in the families such as HMG1 and YB-1 also bound to 15AB. We report them here because several documents have already suggested the possible association of these families and DNA recombination.

Magnetic resonance cholangiopancreatography for diagnosing hepatolithiasis.

BACKGROUND/AIMS: Direct cholangiography with endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography sometimes fails to adequately opacify the entire biliary tract, because of severe biliary obstruction caused by ductal stricture or lodged stones. We assessed the diagnostic accuracy of magnetic resonance cholangiopancreatography for hepatolithiasis. METHODOLOGY: Five patients with hepatolithiasis underwent ultrasonography, computed tomography, direct cholangiography, and magnetic resonance cholangiopancreatography, using a half-Fourier acquisition single-shot turbo spin-echo sequence. Surgical exploration or pathologic examination revealed stricture and dilatation of the intrahepatic ducts in all patients. Diagnostic accuracies for stones and ductal abnormalities were compared among the imaging studies. RESULTS: No complications occurred during magnetic resonance cholangiopancreatography studies. Magnetic resonance cholangiopancreatography fully depicted the biliary tract. Magnetic resonance cholangiopancreatography accurately detected and localized intrahepatic stones, as well as bile duct stricture and dilatation, in all patients. Intrahepatic stones were detected by endoscopic retrograde cholangiopancreatography in one of four patients and by percutaneous transhepatic cholangiography in all three who underwent this procedure. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography demonstrated ductal stricture in all patients but failed to completely demonstrate the biliary tree in three of four patients, and one of three, respectively. On ultrasonography and computed tomography, precise localization of stones was difficult. Ultrasonography and computed tomography failed to demonstrate ductal stricture in one and two of the five patients, respectively. CONCLUSIONS: Magnetic resonance cholangiopancreatography diagnoses intrahepatic stones and bile duct abnormalities less invasively and more accurately than endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography.

Antisense oligonucleotides specific to mutated K-ras genes inhibit invasiveness of human pancreatic cancer cell lines.

BACKGROUND/AIMS: Point mutations of the K-ras gene are detected in > 90% of human pancreatic cancers and may play an important role in tumorigenesis. However, correlations between mutant K-ras and the invasive activity of the tumor have remained unclarified. METHODS: 17-merphosphorothioate antisense oligonucleotides targeting K-ras point mutations were transfected into three kinds of human pancreatic cancer cell lines (MIAPaCa-2, PANC-1, and BxPC-3), and the invasive activity was investigated using an in vitro chemoinvasion assay. RESULTS: Antisense oligonucleotides strongly inhibited the invasive activity of the cell lines with mutant K-ras genes (MIAPaCa-2, PANC-1), but not in that with a wild-type K-ras (BxPC-3). CONCLUSION: Antisense oligonucleotides specific to mutated K-ras genes inhibited the invasiveness of human pancreatic cancer cell lines. Specific antisense therapy to the point mutation of K-ras might be a new anticancer strategy for pancreatic cancer.

Thrombotic thrombocytopenia purpura caused by piperacillin successfully treated with plasma infusion.

An 81-year-old man was admitted to the hospital with a fever and loss of appetite. After treatment with piperacillin sodium (PIPC), the patient exhibited thrombocytopenia, hemorrhagic colitis, and drug-induced skin eruption. On the fifth day after PIPC induction, he further experienced neurological abnormalities, such as disorientation and confusion, renal dysfunction, and microangiopathic hemolytic anemia (MAHA). The patient was diagnosed with thrombotic thrombocytopenic purpura (TTP) on the basis of thrombocytopenia, MAHA, renal dysfunction, fever, and neurological abnormalities. Infusion of fresh-frozen plasma was initiated for treatment. His condition improved markedly after this treatment. It is rare for TTP to be accompanied with hemorrhagic colitis and skin eruption. These symptoms were induced by PIPC and were successfully treated with plasma infusion.

Heterogeneous Sp1 mRNAs in human HepG2 cells include a product of homotypic trans-splicing.

Sp1 is one of the well documented transcription factors, but the whole structure of human Sp1 has not been determined yet. In the present study, we isolated several cDNAs representing two forms of human Sp1 mRNA with different 5'-terminal structures in HepG2 cells. Isolation of a genomic clone established that one of the cDNAs represents the mRNA having consecutive alignment of exons, which allowed deducing the complete amino acid sequence for human Sp1. Another cDNA clone had a surprising structure that possessed an alignment of exons 3-2-3. Both reverse transcriptase-polymerase chain reaction and RNase protection assays confirmed accumulation of the two forms of Sp1 mRNA in HepG2 cells. Because Southern blot analysis suggested that exon 3 is of a single copy in the genome, the cDNA clone having the duplicated sequences for exon 3 appeared to reflect the trans-splicing between pre-mRNAs of human Sp1.

Novel immunogenicity of Oka varicella vaccine vector expressing hepatitis B surface antigen.

Recombinant Oka (ROka) varicella vaccine expressing hepatitis B surface antigen (HBsAg) and subunit HBsAg vaccine (SHV) were used as primary and booster HBsAg vaccines in 3 combinations (SHV-SHV, SHV-ROka, and ROka-SHV) in guinea pigs. Immune responses to HBsAg and varicella-zoster virus gE:gI were evaluated. The 3 combinations induced similar levels of the lymphocyte proliferation response to HBsAg. Of the 3 combinations, SHV-SHV induced the strongest antibody response to an "a" loop of HBsAg and to the whole HBsAg. Its ratio of antibody titer to this loop versus HBsAg was significantly higher than that in SHV-ROka, suggesting the supplementary recognition of the conformational epitope of HBsAg in SHV-ROka. SHV-ROka induced delayed-type hypersensitivity (DTH) to the HBsAg and gE:gI produced in infected cells. Thus, ROka induced DTH to HBsAg and enhanced recognition of the conformational epitope. ROka varicella vaccine may serve as a novel vaccine vector to induce a Th1-type immune response.

Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells.

BACKGROUND/AIMS: Plasminogen activators and plasminogen activator inhibitors are important regulators of the balance between the proteolytic and antiproteolytic activities that determine extracellular matrix turnover. We examined the expression of plasminogen activator-plasmin system components in experimental liver fibrosis of rats. METHODS: Liver fibrosis was produced in rats by injecting carbon tetrachloride for 6 to 12 weeks. Gene expression for plasminogen activator inhibitor-1 (PAI-1), urokinase and tissue plasminogen activators (uPA and tPA), urokinase plasminogen activator receptor (uPAR), and transforming growth factor-beta1 (TGF-beta1) was examined by Northern analysis. Western analysis was performed to detect protein expression of PAI-1, uPA and uPAR. An immunohistochemical study was performed to detect the localization of PAI-1. Additionally, primary cultured liver cells were examined by Northern and Western analyses for this protein with or without prior incubation with TGF-beta1. RESULTS: At 6 weeks, when fibrosis had occurred, uPA and uPAR mRNAs had increased 2.8-fold and 1.8-fold, respectively; PAI-1 and tPA mRNA levels were unchanged. At the cirrhotic stage (9 to 12 weeks), mRNA levels for PAI-1, uPA, uPAR and tPA were all increased. Western analysis also showed increased uPA and uPAR expressions in fibrotic liver, and increased PAI-1, uPA and uPAR expressions in cirrhotic liver. PAI-1 protein was also demonstrated immunohistochemically along sinusoids, vessels, and bile duct cells of normal and fibrotic liver. In liver cell cultures, Kupffer cells, hepatocytes, and especially stellate cells, expressed PAI-1. Expression was enhanced in stellate cells cultured from fibrotic or cirrhotic liver or stimulated in vitro with TGF-beta1. CONCLUSION: Though increased uPA and uPAR may act on matrix degradation in fibrotic liver, increased PAI-1 together with uPA, uPAR and tPA are associated with overall inhibition of matrix degradation in cirrhotic liver. Hepatic stellate cells are an important source of PAI-1 during liver fibrosis.