In both Ath-fed

Wt and foz/foz mice with NASH, Tlrs-4, 7, 9 transcripts increased, with similar pattern for TLR4 and 9 proteins. In Ath-fed Tlr9−/− mice, liver necro-inflammatory score and fibrosis markers were substantially diminished compared with Wt, despite similar steatosis and hepatic lipid levels. Likewise, Ath feeding failed to increase NF-κB and c-Jun activation, macrophage/neutrophil infiltration and pro-inflammatory Th1 cytokines Inhibitor Library mouse in Tlr9−/− mice compared to major increases in Wt. Conversely, expression of anti-inflammatory Th2 cytokines (IL-4, IL-10) was not different. Despite less inflammation in Ath-fed Tlr9−/− vs Wt mice, hepatocyte damage (serum ALT, high mobility group box 1 [HMGB-1], CK-18, asialoglycoprotein [ASGPR] levels) and circulating endotoxin levels were higher. We interpret these changes as reflecting

enhanced necrosis (and/or necroptosis) in response to endotoxemia; correspondingly, Maraviroc order livers showed increased RIP3 (necrosis marker) and MLKL (necroptosis) expression. Further, Tlr9−/− hepatocytes were more susceptible to palmitic acid and endotoxin-induced injury than Wt. Using BM chimeras, we showed that TLR9 in BM-derived myeloid cells and not hepatocytes at least partially mediates Ath diet-induced hepatic injury. This is supported by our observation that, compared to Wt, Tlr9−/− BM-derived macrophages are resistant to activation by CpG DNA, necrotic mediators and LPS induced M1 polarization to produce pro-inflammatory cytokines. Conclusion: These novel data in human liver, in mice with metabolic syndrome-related NASH and with the atherogenic dietary model of NAFLD indicate that TLR9 activation is a critical pro-inflammatory trigger in NASH that is likely mediated via macrophages. In addition, Protein kinase N1 however, TLR9 appears to confer hepatocyte protection in NASH as TLR9-deleted cells are more susceptible to lipotoxicity and endotoxin-induced necrosis. If this is correct, TLR9 blockade may not be an attractive therapeutic approach in NASH because, while it could dampen macrophage activation, it could also abrogate an intrinsic hepatoprotective pathway against

lipotoxic molecules and gut-derived pathogen-associated molecular patterns. B ALZAHRANI,1,2 J GEORGE,1,2 L HEBBARD1,2 1Storr Liver Unit, Westmead Millennium Institute, PO Box 412, Darcy Road, Westmead, NSW 2145, Australia, 2Sydney Medical School, University of Sydney, NSW, Australia Introduction: Liver fibrosis is the scarring process that represents the liver’s response to injury. Adiponectin has been shown to have an important role in the regulation of fibrosis, as adiponectin null mice have greater levels after carbon tetrachloride (CCl4) treatment. Adiponectin binds to three receptors: AdipoR1, AdipoR2 and T-cadherin. Our unpublished studies suggest that AdipoR1 and AdipoR2 null mice have unchanged fibrosis after CCl4 treatment. The role of T-cadherin in hepatic biology is unknown.

In both Ath-fed

Wt and foz/foz mice with NASH, Tlrs-4, 7, 9 transcripts increased, with similar pattern for TLR4 and 9 proteins. In Ath-fed Tlr9−/− mice, liver necro-inflammatory score and fibrosis markers were substantially diminished compared with Wt, despite similar steatosis and hepatic lipid levels. Likewise, Ath feeding failed to increase NF-κB and c-Jun activation, macrophage/neutrophil infiltration and pro-inflammatory Th1 cytokines Talazoparib clinical trial in Tlr9−/− mice compared to major increases in Wt. Conversely, expression of anti-inflammatory Th2 cytokines (IL-4, IL-10) was not different. Despite less inflammation in Ath-fed Tlr9−/− vs Wt mice, hepatocyte damage (serum ALT, high mobility group box 1 [HMGB-1], CK-18, asialoglycoprotein [ASGPR] levels) and circulating endotoxin levels were higher. We interpret these changes as reflecting

enhanced necrosis (and/or necroptosis) in response to endotoxemia; correspondingly, PF-02341066 mw livers showed increased RIP3 (necrosis marker) and MLKL (necroptosis) expression. Further, Tlr9−/− hepatocytes were more susceptible to palmitic acid and endotoxin-induced injury than Wt. Using BM chimeras, we showed that TLR9 in BM-derived myeloid cells and not hepatocytes at least partially mediates Ath diet-induced hepatic injury. This is supported by our observation that, compared to Wt, Tlr9−/− BM-derived macrophages are resistant to activation by CpG DNA, necrotic mediators and LPS induced M1 polarization to produce pro-inflammatory cytokines. Conclusion: These novel data in human liver, in mice with metabolic syndrome-related NASH and with the atherogenic dietary model of NAFLD indicate that TLR9 activation is a critical pro-inflammatory trigger in NASH that is likely mediated via macrophages. In addition, Inositol oxygenase however, TLR9 appears to confer hepatocyte protection in NASH as TLR9-deleted cells are more susceptible to lipotoxicity and endotoxin-induced necrosis. If this is correct, TLR9 blockade may not be an attractive therapeutic approach in NASH because, while it could dampen macrophage activation, it could also abrogate an intrinsic hepatoprotective pathway against

lipotoxic molecules and gut-derived pathogen-associated molecular patterns. B ALZAHRANI,1,2 J GEORGE,1,2 L HEBBARD1,2 1Storr Liver Unit, Westmead Millennium Institute, PO Box 412, Darcy Road, Westmead, NSW 2145, Australia, 2Sydney Medical School, University of Sydney, NSW, Australia Introduction: Liver fibrosis is the scarring process that represents the liver’s response to injury. Adiponectin has been shown to have an important role in the regulation of fibrosis, as adiponectin null mice have greater levels after carbon tetrachloride (CCl4) treatment. Adiponectin binds to three receptors: AdipoR1, AdipoR2 and T-cadherin. Our unpublished studies suggest that AdipoR1 and AdipoR2 null mice have unchanged fibrosis after CCl4 treatment. The role of T-cadherin in hepatic biology is unknown.

The following Abs were used in this study: anti-I-Ab FITC, anti-H-2Kb FITC, anti-CD11c PE, anti-CD8a

PE, anti-CD19 PE, anti-CD1d PE, anti-CD4 PerCP/Cy5.5, anti-CD80 PerCP/Cy5.5, anti-CD11c PerCP/Cy5.5, (Biolegend, San Diego, CA), anti-CD3 FITC, anti-CD86 PE, anti-CD40 PE, Selleckchem Liproxstatin 1 anti-NK1.1 APC (eBioscience, San Diego, CA). For intracellular staining, liver mononuclear cells were incubated with brefeldin A (10 μg/mL) (BD Biosciences, San Diego, CA) at 37°C for 1 hour, then incubated with anti-CD16/32 Abs, followed by staining with PerCP/Cy5.5-conjugated CD3 and PE-conjugated PBS57 loaded CD1d tetramer (originally produced by the NIH tetramer facility, and supplied through Dr. David Serreze), permeabilized with Cytofix/Cytoperm reagent (BD Biosciences), and stained with Alexa Fluor 488-conjugated anti-IFN-γ (clone XMG1.2), Alexa Fluor 488-conjugated anti-IL-4 (clone 11B11), or rat IgG1 isotype control (clone R3-34) (BD Biosciences). Stained cells were assessed on a FACSCalibur (BD Biosciences) using FlowJo softwares (Tree Star, Ashland, OR). Portions of the liver were excised and immediately fixed with 10% buffered formalin solution for 2 days at room temperature. Paraffin-embedded tissue sections

were then cut into 4-μm slices for routine hematoxylin and eosin (H&E), silver, and Azan staining. Scoring of liver inflammation was performed on coded H&E-, silver-, or Azan-stained sections of liver using a set of indices by a “blinded” pathologist (K.T.); these indices selleck chemicals quantitated the degree of portal inflammation, parenchymal inflammation, bile duct damage, granulomas, and fibrosis. Each section was scored as either 0 = no significant change, 1 = minimal, 2 = mild, 3 = moderate, PAK6 and 4 = severe pathology. Details of this scoring system have been described.21 Finally, to detect the presence of alpha-smooth muscle actin (α-SMA)-positive cells, an immunochemical analysis was performed with

a well-characterized monoclonal antibody (mAb) for α-SMA.22 Results are expressed as the mean ± standard error of the mean (SEM). All graphing and statistical analyses were performed using the Prism graphing program (GraphPad Software, San Diego, CA). P-values were calculated using a two-tailed unpaired Mann-Whitney test except in Table 1; the frequency of liver damage in Table 1 was evaluated using Fisher’s exact test. Significance levels were set at P = 0.05. First, to confirm the activity of α-GalCer, a nested substudy was performed in which we intravenously injected α-GalCer to naive mice and analyzed IFN-γ and IL-4 production in serum and in iNKT cells of mice. As shown in Fig. 1A, both IFN-γ and IL-4 were increased in mice injected with α-GalCer. Serum IFN-γ was detectable at 2 hours, peaked at approximately 6 hours, and was maintained until 24 hours after α-GalCer injection, whereas IL-4 peaked at 2 hours and became undetectable after 6 hours (Fig. 1A).

During the 24-month observation, 55 patients

underwent surgery, dental extractions and other invasive procedures (total number of interventions, 126) and therefore received Haemate® P VR as short-term prophylaxis. The procedures were mostly dentistry interventions (52.1%) and invasive procedures/endoscopy (25.6%). The concentrate (infusion of 4 × 103 IU per event, median; 12 × 103 IU per patient, median) was given 60 min (median) before the procedure and after surgery (timing of postoperative treatment was dependent on surgery type and patient bleeding tendency) [Table 4]. These patients received a total PD0325901 in vitro of 234 postoperative, surgery-related infusions (median 7.0 per patient, range 1–19). The median number of postoperative infusions required to treat one event was five (range 1–16). In this subgroup of patients, most events were treated successfully with a response rated as excellent in 56.7% of the events treated (only one patient, with VWD type 2A, had a moderate response to treatment) [Table 4]. The treatment with Haemate® P was generally well-tolerated during the 24-month observation after the switch to the volume-reduced formulation of Haemate® P. There were no reports of adverse reactions related to the

study drug or development of inhibitors against VWF in the entire population, including patients on secondary prophylaxis and thus receiving more infusions. No thrombotic events were reported. During the 24-month follow-up period, almost half of the patients missed days at school/work because of VWD, 36.4% were hospitalized selleck and 35.5% underwent surgery because of the disease (Table 5). The efficacy and safety of Haemate® P for the treatment of VWD in a setting of real-life clinical practice have so far been addressed in a number of retrospective and prospective studies [9, 13-17]. To our knowledge,

Cobimetinib solubility dmso however, this is the first prospective study on a large (121 patients) population of patients with VWD receiving Haemate® P to treat a bleeding episode, as long-term prophylaxis or as short-term prophylaxis for surgery. Treatment history and dosing information was very detailed, and data on patients undergoing surgery/invasive procedures, a treatment setting still under intense investigation, were also collected. Also, the population considered was quite unique in terms of VWD-type distribution, as a relatively high proportion of patients had disease type 3 (31/121), a low prevalence subgroup in the general population of patients with VWD and most severely predisposed to bleeding events due to the virtual absence of VWF [2, 3]. The study population was also assessed in terms of BS, a parameter useful for the objective assessment of disease severity and for guiding therapeutic choices. The high average BS observed clearly indicates that a large proportion of the recruited patients had a significant bleeding tendency, thus strengthening the relevance of the observed results.

This is in contrast with

HCV acquisition in non-haemophilic men, conservatively estimated to occur at age 15 years or later. As duration of HCV infection is a recognized risk factor for HCV progression [1], and, as at least one-fourth of co-infected haemophilic men have Metavir ≥ F3 fibrosis [18], we sought to determine whether transplant outcomes are poorer in co-infected haemophilic than non-haemophilic transplant candidates, within our larger study of OLTX in HIV-infected individuals. The HIV in Solid Organ Transplantation Multisite Study (HIV-TR) is a National Institute of Allergy and Infectious Diseases (NIAID)-funded prospective, observational trial that enrolled transplant candidates

with HIV infection and end-stage liver disease C59 wnt clinical trial (ESLD) from 21 US university transplant centres between October 2003 and February 2010 (NCT00074386). This analysis includes transplant candidates from the eight centres that enrolled both haemophilic and non-haemophilic subjects. Inclusion criteria for the HIV-TR study, previously described [7], include CD4 + cells > 100/μL, or > 200/μL if there was a prior opportunistic infection; and undetectable HIV-1 RNA, or selleck compound predicted HIV suppression in those with hepatotoxicity or cART intolerance. Subjects with a history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis of >1 month duration, primary CNS lymphoma, multidrug resistant fungal infections, or significant wasting were excluded from the study. Patients with hepatocellular carcinoma were excluded from this analysis, as they are typically assigned to a higher priority for liver transplantation regardless of MELD score. Outcomes included transplant, rejection and mortality rates. As exact dates of HCV exposure remain unknown, we assumed HCV exposure occurred with initial clotting factor exposure during the first year of life among those with haemophilia

[17], and with sexual or intravenous Flavopiridol (Alvocidib) drug use exposure at 15 years of age or later, conservatively, among non-haemophilic subjects. Clinical and laboratory data were collected on study subjects at screening, enrolment (time of placement on the transplant waiting list), and every 3 months until transplantation or death, and entered into an online data collection system at each of the participating sites. Clinical variables included age, gender, race, liver disease aetiology, antiretroviral therapy (cART), body mass index (BMI) and cause of death, when appropriate. Laboratory tests included CD4 +  cell count, HIV RNA PCR, HCV RNA PCR and standard chemistry tests, including creatinine and bilirubin, for calculating MELD scores as follows: (MELD = [0.957 × Ln (creatinine mg/dL, maximum 4.0) + 0.378 × Ln (bilirubin mg/dL + 1.120 Ln (INR + 0.643] × 10.

This is in contrast with

HCV acquisition in non-haemophilic men, conservatively estimated to occur at age 15 years or later. As duration of HCV infection is a recognized risk factor for HCV progression [1], and, as at least one-fourth of co-infected haemophilic men have Metavir ≥ F3 fibrosis [18], we sought to determine whether transplant outcomes are poorer in co-infected haemophilic than non-haemophilic transplant candidates, within our larger study of OLTX in HIV-infected individuals. The HIV in Solid Organ Transplantation Multisite Study (HIV-TR) is a National Institute of Allergy and Infectious Diseases (NIAID)-funded prospective, observational trial that enrolled transplant candidates

with HIV infection and end-stage liver disease NVP-BGJ398 solubility dmso (ESLD) from 21 US university transplant centres between October 2003 and February 2010 (NCT00074386). This analysis includes transplant candidates from the eight centres that enrolled both haemophilic and non-haemophilic subjects. Inclusion criteria for the HIV-TR study, previously described [7], include CD4 + cells > 100/μL, or > 200/μL if there was a prior opportunistic infection; and undetectable HIV-1 RNA, or www.selleckchem.com/products/Imatinib-Mesylate.html predicted HIV suppression in those with hepatotoxicity or cART intolerance. Subjects with a history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis of >1 month duration, primary CNS lymphoma, multidrug resistant fungal infections, or significant wasting were excluded from the study. Patients with hepatocellular carcinoma were excluded from this analysis, as they are typically assigned to a higher priority for liver transplantation regardless of MELD score. Outcomes included transplant, rejection and mortality rates. As exact dates of HCV exposure remain unknown, we assumed HCV exposure occurred with initial clotting factor exposure during the first year of life among those with haemophilia

[17], and with sexual or intravenous Exoribonuclease drug use exposure at 15 years of age or later, conservatively, among non-haemophilic subjects. Clinical and laboratory data were collected on study subjects at screening, enrolment (time of placement on the transplant waiting list), and every 3 months until transplantation or death, and entered into an online data collection system at each of the participating sites. Clinical variables included age, gender, race, liver disease aetiology, antiretroviral therapy (cART), body mass index (BMI) and cause of death, when appropriate. Laboratory tests included CD4 +  cell count, HIV RNA PCR, HCV RNA PCR and standard chemistry tests, including creatinine and bilirubin, for calculating MELD scores as follows: (MELD = [0.957 × Ln (creatinine mg/dL, maximum 4.0) + 0.378 × Ln (bilirubin mg/dL + 1.120 Ln (INR + 0.643] × 10.

The final component of LiverTox is an interactive section that allows clinicians to submit a case report or to make suggestions and comments about the website. Submission of a case

requires registration and assignment of a password. Buparlisib price The submission uses a highly structured method with cues to enter the specific information necessary to fully assess the liver injury and judge severity and causality. Information sought includes the name of the drug, dates it was started and stopped, dates of onset of the drug-induced liver injury, pertinent demographic and medical history, initial and serial laboratory tests, and specialized testing and imaging results. The LiverTox website then produces a computer-generated history, a table of serial laboratory results, a graphic display of the course of the illness, and calculations of latency, time to recovery, severity, causality (RUCAM score), and data completeness. The submission can Stem Cells inhibitor also generate an official MedWatch report, if requested, so as to include the case in the official Food and Drug Administration’s (FDA) Adverse Event Reporting System (AERS). Unlike the typical MedWatch report, however, submissions made through LiverTox will be specific for liver-related adverse events and will

provide all of the information necessary to adequately assess liver-related adverse drug events. The submitted cases will be maintained in a searchable database available to the registrants for analysis. This database will

provide a means of monitoring the frequency and secular trends in the incidence of drug induced-liver injury and permits analysis of clinical features and outcomes of the submitted cases. Finally, LiverTox allows for submission of comments regarding Fossariinae the content of the website which will aid in the updating and improvement in the information provided. LiverTox became available online in April 2012 and was released officially as of October 1, 2012. At the time of release, the text of LiverTox contained over one million words, provided information on more than 650 medications, and included over 12,000 annotated references. LiverTox is a work-in-progress and will continue to add new drug records, references, and information in the years ahead. Comments about the accuracy and completeness of LiverTox and suggestions for improvement are welcomed. The creators of LiverTox hope that the website will be a practical and widely used tool for improving diagnosis, management, prevention, and treatment of drug-induced liver disease. The ultimate purpose of LiverTox is to provide a stimulus and structured basis for future clinical and basic research into this important but often neglected cause of liver disease. “
“Mycophenolic acid (MPA) is the activated form of the prodrug mycophenolate mofetil.

Interestingly, both Lcn2Hep-/- and global Lcn2 knockout (Lcn2-/-) mice demonstrated comparable increases in susceptibility to infection MK-1775 with K. pneumoniae or E. coli. These mice also had increased enteric bacterial translocation from the

gut to the mesenteric lymph nodes and exhibited reduced liver regeneration after PHx. Treatment with IL-6 stimulated hepatocytes to produce LCN2 in vitro and in vivo. Hepatocyte-specific ablation of the IL-6 receptor or Stat3, a major downstream effector of IL-6, markedly abrogated LCN2 elevation in vivo. Furthermore, chromatin immunoprecipitation (ChIP) assay revealed that STAT3 was recruited to the promoter region of the Lcn2 Lumacaftor gene upon STAT3 activation by IL-6. In conclusion, hepatocytes are the major cell type responsible for LCN2 production after bacterial infection or PHx, and this response is dependent on IL-6 activation of the STAT3 signaling pathway. Thus, hepatocyte-derived LCN2 plays an important

role in inhibiting bacterial infection and promoting liver regeneration. (Hepatology 2014;) “
“I read with great interest the article by Guerrero et al.,1 who used a large population-based study and several spectroscopic and imaging methodologies to assess the contribution of body fat distribution to the differing rates of hepatic steatosis in the three major US ethnic groups (African American, Hispanic, and Caucasian). They suggested that the differing rates of hepatic steatosis among the

three ethnic groups are associated with similar differences in visceral adiposity. enough Interestingly, in comparison with either Hispanics or Caucasians, African Americans appear to be more resistant to the hypertriglyceridemia associated with insulin resistance despite their lower levels of intraperitoneal and liver fat.1 Here I propose hypovitaminosis D as a potential underlying mechanism for the high prevalence of insulin resistance in African Americans on the basis of the following findings. First, numerous studies have demonstrated that vitamin D insufficiency and hypovitaminosis D are more prevalent among African Americans than other Americans.2-6 This is primarily due to the fact that pigmentation reduces vitamin D production in the skin.2 A cross-sectional analysis of serum 25-hydroxyvitamin D levels showed that hypovitaminosis D was present in a substantial proportion of the studied African American population, even in the South and among those meeting recommended dietary guidelines.5 Moreover, no significant difference was found in the proportion of vitamin D insufficiency between obese and nonobese preadolescent African American children.6 Second, previous studies have established that vitamin D insufficiency and hypovitaminosis D are associated with insulin resistance.

Despite increasing interest and research, there remains uncertainty around the mechanism of HCV-associated cognitive impairment and other CNS effects. Imaging studies have suggested evidence of CNS immune activation[1, 9, 10] and alterations in neurotransmission in HCV infection,[11] yet it is unclear whether this is associated

with a direct effect of viral penetration into the CNS[12] or a result of peripheral factors acting across the blood-brain barrier. HCV genomes have isolated by a number of groups in human microglial cells[13] and recent data show that human brain endothelial cells support productive but low-level infection by HCV.[14] The potential importance of an extrahepatic, immune-privileged site goes beyond the neurocognitive symptoms in this infection, particularly Palbociclib price as we move into the era of interferon-free, direct-acting antiviral therapy. The expected major improvements in sustained virological responses after finite short-course combination therapies will depend on adequate drug penetration to all sites. The era of interferon-free regimens will greatly reduce the neurocognitive burden posed by interferon and offers further opportunities to test the relationships between HCV infection and

CNS symptoms. In the absence of the deleterious effect of interferon, we should expect an accelerated improvement in neurocognitive symptoms if, as suggested, they are directly attributable to find more HCV per se and the promise of high-level, permanent viral eradication

becomes reality. Jasmohan S. Bajaj, M.D., M.Sc.1 “
“Several epidemiological studies have shown that coffee intake attenuates the progression of liver fibrosis; however, the mechanism is unclear. We investigated the direct effects of caffeine on hepatic stellate cells (HSCs) and assessed whether caffeine attenuated intrahepatic fibrosis in rat model of liver cirrhosis. Human hepatic stellate cell line, an immortalized human HSCs line, was used in in vitro assay system. Cell migration and proliferation were assessed in presence of various caffeine concentrations (0, 1, 5, and 10 mmol), and Montelukast Sodium levels of procollagen type Ic and α-smooth muscle actin (α-SMA) were measured by Western blot. Severity of liver inflammation and fibrosis were compared between thioacetamide-treated rats with and without caffeine supplementation. Caffeine increased HSCs apoptosis and intracellular F-actin and cyclic adenosine monophosphate expression. Caffeine also inhibited procollagen type Ic and α-SMA expression in a dose- and time-dependent manner. In rat model, caffeine decreased periportal inflammation, levels of inflammatory cells (1.4 ± 0.52 vs 2.6 ± 0.46, P < 0.05), and fibrosis (2.1 ± 0.35 vs 2.9 ± 0.84, P < 0.05). Transforming growth factor-β and α-SMA expressions were also reduced by caffeine. Caffeine attenuates the progression of liver fibrosis by inhibiting HSCs adhesion and activation.

Despite increasing interest and research, there remains uncertainty around the mechanism of HCV-associated cognitive impairment and other CNS effects. Imaging studies have suggested evidence of CNS immune activation[1, 9, 10] and alterations in neurotransmission in HCV infection,[11] yet it is unclear whether this is associated

with a direct effect of viral penetration into the CNS[12] or a result of peripheral factors acting across the blood-brain barrier. HCV genomes have isolated by a number of groups in human microglial cells[13] and recent data show that human brain endothelial cells support productive but low-level infection by HCV.[14] The potential importance of an extrahepatic, immune-privileged site goes beyond the neurocognitive symptoms in this infection, particularly selleck kinase inhibitor as we move into the era of interferon-free, direct-acting antiviral therapy. The expected major improvements in sustained virological responses after finite short-course combination therapies will depend on adequate drug penetration to all sites. The era of interferon-free regimens will greatly reduce the neurocognitive burden posed by interferon and offers further opportunities to test the relationships between HCV infection and

CNS symptoms. In the absence of the deleterious effect of interferon, we should expect an accelerated improvement in neurocognitive symptoms if, as suggested, they are directly attributable to selleckchem HCV per se and the promise of high-level, permanent viral eradication

becomes reality. Jasmohan S. Bajaj, M.D., M.Sc.1 “
“Several epidemiological studies have shown that coffee intake attenuates the progression of liver fibrosis; however, the mechanism is unclear. We investigated the direct effects of caffeine on hepatic stellate cells (HSCs) and assessed whether caffeine attenuated intrahepatic fibrosis in rat model of liver cirrhosis. Human hepatic stellate cell line, an immortalized human HSCs line, was used in in vitro assay system. Cell migration and proliferation were assessed in presence of various caffeine concentrations (0, 1, 5, and 10 mmol), and Exoribonuclease levels of procollagen type Ic and α-smooth muscle actin (α-SMA) were measured by Western blot. Severity of liver inflammation and fibrosis were compared between thioacetamide-treated rats with and without caffeine supplementation. Caffeine increased HSCs apoptosis and intracellular F-actin and cyclic adenosine monophosphate expression. Caffeine also inhibited procollagen type Ic and α-SMA expression in a dose- and time-dependent manner. In rat model, caffeine decreased periportal inflammation, levels of inflammatory cells (1.4 ± 0.52 vs 2.6 ± 0.46, P < 0.05), and fibrosis (2.1 ± 0.35 vs 2.9 ± 0.84, P < 0.05). Transforming growth factor-β and α-SMA expressions were also reduced by caffeine. Caffeine attenuates the progression of liver fibrosis by inhibiting HSCs adhesion and activation.