Patients underwent imaging every 6 weeks to assess radiographic

time-to-tumor progression (TTP). Patients were also assessed for symptomatic endpoints based on a questionnaire. The primary endpoints to the study were overall survival (OS) and the time to symptomatic progression. This study was the first to demonstrate a significant improvement in overall survival with a median OS of 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio = 0.69; 95% confidence interval = 0.55-0.87; P < 0.001). There was no significant www.selleckchem.com/HSP-90.html difference in the time to symptomatic progression. The median TTP which was 2.8 months in the placebo group increased to 5.5 months in the sorafenib group (P < 0.001). Interestingly, this benefit was not driven by an increase in tumor shrinkage on imaging using standard clinical trial criteria, suggesting the benefit was largely driven by inducing stable disease and slowing progression. Common and predictable toxicities in this population included hand-foot skin reaction, anorexia, and diarrhea. These are highlighted in Table 1. Of note, there was no significant difference in changes in liver dysfunction or bleeding events between the two groups. 76% of patients in the sorafenib group

received more than 80% of the planned daily dose. Importantly, the control group in this study clearly defined the natural history of patients with untreated BCLC Stage C HCC and Child A cirrhosis. Crizotinib supplier The tandem study to SHARP, performed in Asia, evaluated the role of sorafenib in a predominantly hepatitis B population.21 The dosage of sorafenib was the same and again only patients with Child A cirrhosis

were selected. Similar to the SHARP study, sorafenib improved OS (6.5 months for patients treated with sorafenib, compared with 上海皓元 4.2 months in the placebo group (hazard ratio = 0.68; 95% confidence interval = 5.56-7.56; P = 0.014) and median TTP was 2.8 months in the sorafenib treated group compared to 1.4 months in the placebo group (P = 0.0005). Although the magnitude of benefit was the same in both studies as represented by the hazard ratios of 0.69 and 0.68, respectively, both control and treated groups in the Asian study had a lower survival than the corresponding arms in the SHARP study. One explanation for this it the fact that more of the patients in the Asian study had BCLC C stage than in SHARP, which included a population of BCLC stage B patients. Again, the toxicities seen in the Asian study were similar to the SHARP study though there was an increased incidence of any grade hand-foot skin reaction, 45% in Asia versus 21% in SHARP. Based on the data above, sorafenib has become the standard of care for patients with advanced HCC. The median improvement of 3 months in survival and 30% reduction on the risk of death is a significant first step in the management of this group of patients.

reported that serum PG I and II level, but not PG I/II ratio, were significantly higher in serum CagA antibody positive compared with negative children.[26] Serum PG was reported to be correlated with gastric inflammatory score.[27] In addition, the cagA status was reported to be associated with various kinds of cytokines including interleukin-8 (IL-8) and may cause severe inflammation

in the stomach.[28] It is also possible that gastritis increases Selleck PLX4032 permeability of the gastric epithelial surface, enabling back diffusion of PGs after secretion.[27] These findings suggest that serum CagA antibody titer was associated with gastric inflammation, but not atrophy. Shimoyama et al. reported that inflammation in the antrum and the corpus was more significant in serum CagA antibody positive when they examined the presence of serum CagA antibody by

immunoblot.[29] In the present study, although there were no significant differences of each histological score between serum CagA antibody positive and negative GSK126 clinical trial group, the mucosal inflammation in the corpus was significantly correlated with serum CagA antibody titer. This finding also supported that different level of antibody production from lymphocytes induced by H. pylori infection can contribute to the various serum CagA antibody level. Interestingly, positive correlation between the inflammatory score and serum CagA antibody titer was found only in the corpus but not in the antrum. Corpus dominant gastritis rather than antrum dominant gastritis was a risk factor to develop gastric ulcer and gastric cancer.[3, 30] In addition, even when only serum CagA antibody positive group was selected, serum CagA antibody titer was significantly correlated with inflammation and activity in the corpus. Therefore, antibody titer rather than the presence of antibody can be a useful marker for advanced inflammation in the stomach in Japan. This suggests that serum CagA antibody titer might be an available marker to predict 上海皓元医药股份有限公司 a gastric cancer in Japan. It has also been reported that measurement of serum levels of C-reactive protein (CRP) using a high-sensitivity assay (hs-CRP) can reveal

subclinical inflammatory states that may reflect vascular inflammation.[31] Recent report showed that the mean serum level of hs-CRP was significantly higher in H. pylori-positive group than H. pylori-negative group, although the level of hs-CRP was not different between CagA antibody positive and negative group in Iran.[32] It is better to examine the association between serum CagA antibody and hs-CRP in Japan in the further study. In our study, in spite of cagA positive by PCR, the prevalence of serum CagA antibody was 75.0%, which was consistent with previous studies from Japan.[17, 33] The cagA gene is located at one end of the cag pathogenicity island (PAI), an approximately 40-kbp region that is thought to have been incorporated into the H. pylori genome by horizontal transfer from an unknown source.

Multiple comparisons were analyzed using the ANOVA test with Bonferroni correction. All reported P values are two-sided, and P values lower

than 0.05 are considered to indicate significance. All calculations were performed using the SPSS 16.0 software (SPSS, Inc., Chicago, IL). A total series of 62 patients was included in the study. Of those, 22 patients had SBP, either with a positive (n = 9) or negative (n = 13) culture. No clinical or analytical statistically significant differences were observed between culture-positive and culture-negative patients with SBP. Bacterial DNA was identified in all 22 patients with SBP, regardless of their microbiological PF-02341066 research buy culture. Identified bacterial species were Escherichia coli (n = 12), Staphylococcus aureus (n = 4), Streptococcus spp. (n = 3), Klebsiella pneumoniae (n = 2), and Enterococcus faecalis (n = 1). No differences were observed in the proportion of gram-negative and gram-positive sequencing-identified microorganisms between culture-negative

and culture-positive patients with SBP. Among patients with culture-positive SBP (n = 9), the culture-isolated microorganisms corresponded to those identified by nucleotide sequencing selleckchem in all cases, except one identified as Staphylococcus aureus by sequencing but as Streptococcus pneumoniae by microbiological culture. Mean amplified bacterial DNA concentration was 32.1 ± 8.6 ng/μL medchemexpress and mean serum endotoxin levels were 1.46 ± 0.65 endotoxin units (UE)/mL. Twenty patients with cirrhosis and ASC, as determined by positive microbiological culture or bacterial DNA presence in blood and AF,

who were not receiving SID with norfloxacin constituted Group II. Serum endotoxin levels within this group were 0.35 ± 0.06 UE/mL (P < 0.05 compared with SBP group). Finally, 20 patients with cirrhosis and ascites who were undergoing SID with norfloxacin as secondary prophylaxis of SBP were also included. The period of norfloxacin administration was shorter than 14 months in all patients. Bacterial DNA was not found in any sample in this group, and serum mean endotoxin levels were 0.32 ± 0.05 UE/mL (P < 0.05 compared with SBP patients). Patients’ clinical and analytical characteristics are shown in detail in Table 1. Mean age of included patients was 58 years, and 61% of them were male. Total white blood cells and PMN cells in AF were statistically increased in the overall series of SBP versus the rest of the patients. Sixteen of 22 patients with SBP, four of 20 patients with ASC, and all patients undergoing SID with norfloxacin had had previous episodes of ascites. Three patients with SBP, two patients with ASC and two patients undergoing SID had had previous episodes of encephalopathy. A 6-month period of follow-up was studied in all patients. Four patients with SBP, two patients with ASC, and three patients undergoing SID died during the follow-up.

We also explored the impact of acute, rather than chronic Klf6 depletion, by treating primary hepatocytes from Klf6fl(+/+) mice with either LacZ- or AdenoCre virus to deplete Klf6 in culture, and additionally treating cells with either pBabe- or pBabeSV1 lentivirus to overexpress SV1 in order to recapitulate the phenotypes of the four different mouse lines. This approach yielded a consistent Klf6 mRNA depletion of ≈50% and ≈5-fold overexpression of SV1, as assessed by quantitative PCR (Supporting

Fig. 3A-C). Primary hepatocytes from both chronic (AlbCre Klf6fl(+/+)) and acute (Klf6fl(+/+) and adenoCre virus) Klf6-depleted hepatocytes displayed a significant increase in DNA synthesis, based on 3H-thymidine incorporation assay (Fig. 4A, P < 0.05; 4B, P < 0.05). Although SV1 overexpression in hepatocytes both from SV1 transgenic animals and pBabeSV1-infected Klf6fl(+/+) hepatocytes only click here buy CP-868596 displayed a trend toward increased 3H-thymidine incorporation,

the combination of Klf6 depletion and SV1 overexpression led to an additional and significant increase in DNA synthesis in both models (Fig. 4A, P < 0.05; 4B, P < 0.0005). These findings correlated with a significantly increased hepatocyte count from either SV1 Klf6fl(+/+) transgenics 24 hours after isolation (P < 0.05), and of AlbCre Klf6fl(+/+)- (P < 0.05) or SV1 AlbCre Klf6fl(+/+) hepatocytes (P < 0.02) 48 hours after isolation (Fig. 4C). Thus, Klf6 depletion increases proliferation, which is further augmented when SV1 is simultaneously overexpressed. To examine if SV1 overexpression or Klf6 depletion had an impact on cell cycle distribution, we performed FACS analysis of primary hepatocytes. There was a significant increase of cells with 4N DNA, but without any measurable differences in S-phase distribution (Fig. 5A) in SV1 overexpressing MCE公司 and/or Klf6 depleted cells compared to Klf6 wildtype hepatocytes. This corresponded with very few PCNA-positive hepatocytes in untreated hepatocytes of all four murine models

(Supporting Fig. 4A,B). The increased number of 4N cells was consistent with an increase in cell ploidy, which was confirmed by nuclear quantification per cell (Fig. 5B,C). The control mice had significantly more cells with a single nucleus at baseline compared with the SV1 transgenic or Klf6-depleted hepatocytes. Forty-eight hours after isolation there was a shift toward higher ploidy of the hepatocytes in all groups. This shift was significant for hepatocytes from SV1 AlbCre Klf6fl(+/+) mice (P < 0.05) (Fig. 4B). The increased ploidy is DEN-independent, as it was observed in hepatocytes isolated from untreated mice and in age-matched animals between 10-12 weeks of age. Cyclin B1, which is a key regulator of G2/M transition, was consistently down-regulated in SV1-transgenic and Klf6-depleted hepatocytes, indicating reduced G2/M transition in the SV1-transgenic and Klf6-depleted hepatocytes (Supporting Fig. 5). We next examined how SV1 antagonizes KLF6 tumor suppressor function.

Gregg Duester (Sanford-Burnham Medical Research Institute, La Jolla, CA). The mice were bred in a CAL-101 in vivo specific pathogen-free facility (Bio Model System Park; KAIST, Daejeon, Korea). All animal experiments were approved by KAIST Institutional Animal Care and Use Committee. To induce liver fibrosis, 8- to 10-week-old mice were treated with 0.4 mL/kg carbon tetrachloride (CCl4) diluted in olive oil via intraperitoneal injection three times per week for 2 weeks. Twenty-four

hours after the last injection of CCl4, 1 × 106 whole BMCs or control medium were transferred to mice via the tail vein. Twelve or 24 hours after infusion of BMCs, mice were sacrificed. Human BMCs were harvested from patients with HBV-induced liver cirrhosis for autologous BMC infusion in Severance Hospital (Seoul, Korea). Some BMCs were used for in vitro experiments with the patients’ consent. Serum data were obtained from patients treated with autologous BMC infusion between November 2006 and February 2008. The protocol for the clinical trial conformed to the ethical guidelines of the Declaration of Helsinki and was approved

by the Institutional Review Board of Severance Hospital in the Yonsei University Health BI 2536 clinical trial System. Data are expressed as the mean ± SEM. To compare values, a Student t test or analysis of variance was performed. For blood samples of patients, a Wilcoxon signed-rank test with Bonferroni correction was used to compare the values of paired samples. P < 0.05 was considered statistically significant. All other materials and methods are described in the Supporting Information. To investigate early events following infusion of BMCs in fibrotic liver, mice with CCl4-induced liver

fibrosis were sacrificed at 12 and 24 hours after infusion with BMCs from GFP+ mice via the tail vein. At 12 and 24 hours, serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, albumin, cholesterol, and glucose were not changed compared with those of vehicle-infused mice (Fig. 1A and MCE Supporting Fig.1A). However, collagen fibers and α-smooth muscle actin (α-SMA)–positive HSCs in liver tissues of BMC-infused mice were decreased compared with those of vehicle-infused mice at 12 and 24 hours (Fig. 1B and Supporting Fig. 1B), which were confirmed by western blotting (Fig. 1C) and quantitative RT-PCR (qRT-PCR) analyses (Fig. 1D) in isolated HSCs. In contrast, relative messenger RNA (mRNA) levels in HSCs for TGF-β1, IL-6, and monocyte chemoattractant protein-1 (MCP-1) were decreased only at 24 hours in BMC-infused mice but not in vehicle-infused mice, whereas there was no significant difference in IL-10 mRNA expression in HSCs (Supporting Fig. 1C). More surprisingly, most migrated GFP+ BMCs were in close contact with activated HSCs in the fibrotic septa within 24 hours (Fig. 1E and Supporting Fig. 1D).

The consequent definition of non–life-threatening bleeding episodes that are non-responsive to bypassing treatment provides a global picture of the condition of the patient during such an event. Identification of non-responsiveness is based on various criteria: pain, swelling/tension, mobility, patient perception and laboratory parameters. Criteria can be assessed subjectively by the patient/parent and/or objectively by the clinician.

Although the precise timing of each determination should be at the discretion of the physician, bleeds should be considered non-responsive if the clinical situation meets the specified criteria 24 h from PF-6463922 solubility dmso the start of treatment. Although it is not intended to replace clinical judgment, this definition can guide the optimal course of treatment for patients with haemophilia

and inhibitors. “
“Summary.  Antibody responses to clotting factor concentrates remain a major treatment limitation. In conjucation with ongoing clinical studies, the pathogenesis and potential treatment of clotting factor immune responses is being evaluated in a variety of animal models. In 2010, the most important treatment-related complication of coagulation factor replacement is the development of neutralizing antibodies to the therapeutic protein. This complication occurs in approximately 25% of haemophilia selleck compound A (HA) patients and 3% of haemophilia B subjects. While significant progress has been made in our understanding of the pathogenic mechanisms involved in this phenomenon, much remains to be learnt. The investigation of the immune MCE公司 response to coagulation factor exposure in human haemophiliacs is limited by a number of biological and practical considerations. Thus, while it remains critical to continue the evaluation of this treatment complication in human populations, this experimental approach will need to be complemented with

observations made in animal models of haemophilia. This chapter focuses on three specific aspects of the immune response to factors VIII (FVIII) and factor IX (FIX): the development of novel transgenic mouse models to facilitate the characterization of this process, the study of tolerance mechanisms in haemophilic mice and finally, the association of inhibitors with haemophilia gene therapy studies. About 25% of patients with severe HA develop neutralizing antibodies against FVIII, after replacement therapy [1,2]. The antibody response to FVIII is a polyclonal IgG response that is not restricted isotypically. Although IgG4 is frequently the major component of anti-FVIII antibodies, all IgG subclasses have been found [3,4]. While the antibodies against FVIII are well characterized [5–8], limited information is available on the regulation of the antibody response. In particular, the reason why some patients develop antibodies while others do not is far from clear.

They are particularly useful for the arterial phase. Contrast media are also highly

useful for the delayed phase of CT. (grade A) Based on studies using CTHA, it has been known for a very long time that clinically malignant hepatocellular carcinomas show greater arterial blood flow than the surrounding liver tissue (LF062091 level 3). In CO2 ultrasound angiography, the mean doubling time of tumors with increased arterial blood flow was 70 days, and the mean doubling time of nodules with a poor arterial blood flow was 370 days; thus, hypovascular tumors see more have been reported to grow more slowly (LJ033682 level 3). In recent studies using CTHA and CTAP, a correlation between the histological degree of differentiation (e.g. dysplastic nodule to well-differentiated hepatocellular carcinoma, moderately- or poorly-differentiated hepatocellular carcinoma) and the tumor vascularity has been demonstrated, reflecting the multistage growth of hepatocellular carcinoma (LF062043 level 2a, LF057244 level 2a). Hepatocellular carcinomas with increased arterial blood flow may be the main targets of diagnosis and treatment. Dynamic studies using iodine-enhanced CT and extracellular Gd-enhanced MRI improve the detection rate

of hypervascular hepatocellular carcinomas. In a study check details using early-period angiographic findings as the standard, a diagnosis was made in 88% of the cases based on a combination of non-contrast CT and arterial phase CT (LF025385 level 1). A subsequent study revealed that addition of a delayed phase to the arterial phase increased the diagnostic rate of CT (LF057106 level 1). Dynamic MRI study has also been demonstrated to be highly useful among imaging techniques, and the arterial phase is quite important for detecting hypervascular hepatocellular carcinomas MCE公司 (LF058397 level 1). In a study of the livers of liver

transplant recipients, the detection rates of hepatocellular carcinoma were 76.9% for high-resolution MRI, 53.8% for single helical CT and 46.2% for ultrasonography, showing the superiority of MRI (LF020018 level 1). For minimizing individual differences in the appropriate timing of imaging of the arterial phase, the time required for contrast injection should be fixed for all contrast media (LF120829 level 2a). Superparamagnetic iron oxide used for MRI is taken up by reticuloendothelial cells, leading to a decrease in the signal intensity of the liver parenchyma. Reticuloendothelial cells are not present in a tumor, and the signal intensity does not decrease. Diagnosis is made based on these characteristics. A good degree of correlation has been reported between the degree of differentiation of hepatocellular carcinoma and the SPIO uptake in SPIO-MRI (LF0620210 level 3). When focusing only on the detection capability of hepatocellular carcinoma, the extracellular Gd contrast agent is superior to SPIO (LF0218211 level 1, LF0573412 level 1).

They are particularly useful for the arterial phase. Contrast media are also highly

useful for the delayed phase of CT. (grade A) Based on studies using CTHA, it has been known for a very long time that clinically malignant hepatocellular carcinomas show greater arterial blood flow than the surrounding liver tissue (LF062091 level 3). In CO2 ultrasound angiography, the mean doubling time of tumors with increased arterial blood flow was 70 days, and the mean doubling time of nodules with a poor arterial blood flow was 370 days; thus, hypovascular tumors Doxorubicin purchase have been reported to grow more slowly (LJ033682 level 3). In recent studies using CTHA and CTAP, a correlation between the histological degree of differentiation (e.g. dysplastic nodule to well-differentiated hepatocellular carcinoma, moderately- or poorly-differentiated hepatocellular carcinoma) and the tumor vascularity has been demonstrated, reflecting the multistage growth of hepatocellular carcinoma (LF062043 level 2a, LF057244 level 2a). Hepatocellular carcinomas with increased arterial blood flow may be the main targets of diagnosis and treatment. Dynamic studies using iodine-enhanced CT and extracellular Gd-enhanced MRI improve the detection rate

of hypervascular hepatocellular carcinomas. In a study Vismodegib in vitro using early-period angiographic findings as the standard, a diagnosis was made in 88% of the cases based on a combination of non-contrast CT and arterial phase CT (LF025385 level 1). A subsequent study revealed that addition of a delayed phase to the arterial phase increased the diagnostic rate of CT (LF057106 level 1). Dynamic MRI study has also been demonstrated to be highly useful among imaging techniques, and the arterial phase is quite important for detecting hypervascular hepatocellular carcinomas MCE公司 (LF058397 level 1). In a study of the livers of liver

transplant recipients, the detection rates of hepatocellular carcinoma were 76.9% for high-resolution MRI, 53.8% for single helical CT and 46.2% for ultrasonography, showing the superiority of MRI (LF020018 level 1). For minimizing individual differences in the appropriate timing of imaging of the arterial phase, the time required for contrast injection should be fixed for all contrast media (LF120829 level 2a). Superparamagnetic iron oxide used for MRI is taken up by reticuloendothelial cells, leading to a decrease in the signal intensity of the liver parenchyma. Reticuloendothelial cells are not present in a tumor, and the signal intensity does not decrease. Diagnosis is made based on these characteristics. A good degree of correlation has been reported between the degree of differentiation of hepatocellular carcinoma and the SPIO uptake in SPIO-MRI (LF0620210 level 3). When focusing only on the detection capability of hepatocellular carcinoma, the extracellular Gd contrast agent is superior to SPIO (LF0218211 level 1, LF0573412 level 1).

[58] This reduction in iron export capacity most significantly

affects cells of the reticuloendothelial system, namely macrophages, which are responsible for the recycling of iron from quiescent red blood cells. This reduces the recycling of iron, resulting in macrophage iron loading within the liver and spleen. This reduced capacity for iron recycling also results in transferrin saturation usually toward the lower end of the normal range. As a result of the reduced capacity of cells to export iron and thus mobilize iron stores, aggressive venesection can lead to anemia Inhibitor Library mouse in these patients even in the presence of persisting iron overload.[59] Mutations that lead to non-classical ferroportin disease result in ferroportin protein that is resistant to hepcidin-induced internalization.[60]

The interaction of hepcidin with ferroportin is the key event in controlling iron homeostasis. When a mutation prevents this interaction or internalization after hepcidin binding, the ferroportin protein remains at the cell surface, constitutively exporting iron. This persistent ferroportin activity in enterocytes of the duodenum and in reticuloendothelial macrophages results in increased dietary iron absorption and recycling, eventually resulting in parenchymal iron accumulation. This is essentially the same situation that occurs in the autosomal recessive forms of HH that result from hepcidin deficiency. Because of this commonality in the iron loading mechanism, the phenotypic presentation buy Adriamycin of non-classical ferroportin disease is indistinguishable from HFE and TFR2-HH. Over 30 mutations associated with iron overload have been reported in the ferroportin gene. Ferroportin disease has a worldwide distribution. The first description of a non-HLA

linked form of iron overload with possible autosomal dominant inheritance was in a Melanesian pedigree from the Solomon Islands,[61] and since then, many MCE公司 of the reported cases have been in the Asia-Pacific region (Fig. 2). It now seems likely that the iron overload disease present in the Solomon Islands is the non-classical form of ferroportin disease caused by the N144T mutation.[62] Some mutations have been reported in Australian and New Zealand individuals with European backgrounds. Such mutations include A77D[63] and V162del,[64] which are associated with classical disease, and N144D[65] and S338R[66] associated with non-classical disease. The V162del mutation is the most common mutation reported in ferroportin. It has been detected in several geographically distinct populations including in a female Sri Lankan.[67] The A77D mutation has also been reported in Indian patients with thalassemia major; unusually, one patient was reported to be homozygous for this mutation, although no further explanation was given.

The regulation of MMP-12 elastin degradation was defined mechanistically CX-4945 using CD11b-DTR and MMP-12 knockout mice. In a CCl4 model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced

versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl4 in MMP-12−/− mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12−/− mice compared with WT. Conclusion: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive

experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies. (HEPATOLOGY 2012;55:1965–1975) Liver fibrosis and its endstage, cirrhosis, MK-8669 in vivo represent a major worldwide health problem.1 Although removal of the underlying injurious process (e.g., with antiviral therapy) may halt the progression of liver fibrosis, liver transplantation remains the only effective treatment for advanced fibrosis and cirrhosis. Unfortunately, the limited supply of donor organs restricts the availability of this treatment. In recent years, studies in rodents2-4 corroborated by sequential study of human liver cirrhosis5 have led to a paradigm shift in the understanding of fibrosis reversibility: both advanced fibrosis medchemexpress and cirrhosis, previously considered

irreversible, are at least partly reversible following withdrawal of the injurious stimulus. The development of liver fibrosis is associated with profound changes in both the biochemical composition and physical properties of the extracellular matrix. It is now clear that hepatic stellate cells (HSCs) are a major contributor to hepatic myofibroblasts, which represent the key effector cell population in the development of fibrosis, secreting fibrillar collagens and other matrix components, including elastin.6-8 Despite the concurrent expression of matrix degrading metalloproteinases (MMPs), net matrix accumulation occurs in the injured liver, in major part as a result of expression of the potent tissue inhibitors of metalloproteinases (TIMPs 1 and 2) by HSC.9, 10 Previous fibrosis studies have focused almost exclusively on secretion and turnover of collagens. However, other matrix components play critical roles in the development and progression of fibrosis.