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Juan Rodés

Publications and source records attributed to Juan Rodés.

At least 19 recordsLinked to original sources
PubMed2006

Impaired extracellular matrix degradation in aortic vessels of cirrhotic rats.

BACKGROUND/AIMS: Thinning of the vascular wall occurs in conductance vessels of cirrhotic rats. Increased nitric oxide synthase (NOS) activity has been involved in the pathogenesis of this phenomenon. Therefore, we assessed the NO-regulated cell signaling pathways participating in vascular remodeling in cirrhosis. METHODS: Aortas were obtained from 15 control and 15 cirrhotic rats. Phosphorylated p38 MAPK and ERK1/2 were used to evaluate the activation of cell MAPK signaling pathways. Extracellular matrix (ECM) turnover was estimated by measuring matrix metalloproteinases (MMPs) activity and protein expression of collagen IV, MMP-2, MMP-9 and tissue inhibitor of MMPs (TIMP)-2. Thereafter, 12 control and 12 cirrhotic rats received Nomega-nitro-L-arginine-methyl-ester or vehicle daily for 11 weeks. RESULTS: Cirrhotic vessels showed a reduction in ERK1/2 phosphorylation, lower MMP activity, decreased MMPs expression and higher collagen IV and TIMP-2 abundance, compared to control rats. Chronic NOS inhibition normalized ERK1/2 phosphorylation and MMPs activity, increased MMPs abundance and decreased TIMP-2 expression in cirrhotic rats. CONCLUSIONS: Vascular remodeling in cirrhotic rats is mediated by down-regulation of cell growth and impaired ERK1/2 activation and subsequent imbalance of ECM turnover. These results further stress the importance of vascular NO overactivity in the reduction of vascular wall thickness in cirrhosis.

Animals↗
PubMed2006

Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S-hydroxy-DHA.

Docosahexaenoic acid (DHA) is a omega-3 essential fatty acid that reduces the incidence and severity of a number of diseases. Recently, a novel series of DHA-derived lipid mediators with potent protective actions has been identified. In this study we demonstrate that dietary amplification of these DHA-derived products protects the liver from necroinflammatory injury. In vitro, supplementation of hepatocytes with DHA significantly reduced hydrogen peroxide-induced DNA damage, evaluated by the "comet assay," and oxidative stress, determined by measurement of malondialdehyde levels. In vivo, dietary supplementation of mice with DHA ameliorated carbon tetrachloride-induced necroinflammatory damage. In addition, hepatic cyclooxygenase-2 expression and PGE2 levels were significantly reduced in mice fed DHA-enriched diets. In these animals, increased hepatic formation of DHA-derived lipid mediators (i.e., 17S-hydroxy-DHA (17S-HDHA) and protectin D1) was detected by HPLC-gas chromatography/mass spectrometry analysis. Consistent with these findings, synthetic 17-HDHA abrogated genotoxic and oxidative damage in hepatocytes and decreased TNF-alpha release and 5-lipoxygenase expression in macrophages. In a transactivation assay, 17-HDHA acted in a concentration-dependent manner as a PPARgamma agonist. Taken together, these findings identify a potential role for DHA-derived products, specifically 17S-HDHA and protectin D1, in mediating the protective effects of dietary DHA in necroinflammatory liver injury.

Animals↗
PubMed2006

Gene expression profiling of renal dysfunction in rats with experimental cirrhosis.

BACKGROUND/AIMS: Renal dysfunction is a frequent complication in advanced cirrhosis. The mechanisms underlying this complication have classically been addressed through conventional methods of study of candidate genes, but never on a genome-wide scale. In this investigation, we used microarrays to monitor global gene expression changes in the kidney of cirrhotic rats. METHODS: Renal samples were obtained from control and carbon tetrachloride-induced cirrhotic rats. RNA samples were reverse-transcribed into Cy5-labeled cDNA, combined with a Cy3-labeled reference and hybridized to oligonucleotide microarrays. Microarrays were scanned in a Genepix 4000B and data analyzed by Luminator v2.0 software. RESULTS: A total of 620 genes were differentially regulated (354 up and 266 down) in the cirrhotic kidney, accounting for approximately 11% of all analyzed transcripts. Functional grouping of these genes revealed that 47 were related to the category of vascular tone and 85 to transporters/channels. Among these, we identified genes and pathways already associated with renal dysfunction as well as a new subset of genes previously unknown to participate in this complication, including a G protein-coupled receptor that binds apelin, a protein phosphatase (calcineurin B) and a number of neuropeptide receptors and growth factors. CONCLUSIONS: These findings furnish new data for mechanistic investigation into renal dysfunction in cirrhosis.

Animals↗
PubMed2006

Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid.

BACKGROUND & AIMS: Because the efficacy of UDCA on long-term outcome of primary biliary cirrhosis (PBC) has not been completely elucidated, we have assessed the course and survival of patients with PBC treated with UDCA and compared with the survival predicted by the Mayo model and the estimated survival of a standardized population. METHODS: (One hundred ninety-two patients [181 women] with PBC treated with UDCA [15 mg/kg per day] for 1.5-14 years.) Response to treatment was defined by an alkaline phosphatase decrease greater than 40% of baseline values or normal levels after 1 year of treatment. The predicted survival was obtained by the Mayo model and the estimated survival was taken from the standardized matched Spanish population. RESULTS: Seventeen patients died or fulfilled criteria for liver transplantation (8.9%). The observed survival was higher than that predicted by the Mayo model and lower than that of the control population (P < .001). One hundred seventeen patients (61%) responded to treatment. The survival of responders was significantly higher than that predicted by the Mayo model and similar to that estimated for the control population (P = .15). By contrast, the survival of patients without biochemical response was lower than that estimated for the Spanish population (P < .001) although higher than that predicted by the Mayo model. CONCLUSIONS: Biochemical response to UDCA after 1 year is associated with a similar survival to the matched control population, clearly supporting the favorable effects of this treatment in PBC. The suboptimal survival of nonresponders identifies the group for further treatments.

Alkaline Phosphatase↗
PubMed2006

Characterization and differentiation of autoimmune versus viral liver involvement in patients with Sjögren's syndrome.

OBJECTIVE: To analyze the prevalence and clinical significance of liver involvement in patients with Sjögren's syndrome (SS), focusing on the characterization and differentiation of autoimmune versus chronic viral liver disease. METHODS: We investigated liver involvement (clinical signs, analytical data, chronic viral infections, and autoantibodies) in 475 consecutive patients with SS. All patients fulfilled 4 or more of the 1993 European Community Study Group criteria for SS. RESULTS: Liver involvement was detected in 129 (27%) patients. After ruling out chronic illnesses or use of hepatotoxic drugs, the main etiologies were chronic viral liver disease in 64 (13%) cases [chronic hepatitis C virus (HCV) infection in 63 and HBV infection in one] and autoimmune liver diseases in 24 (5%; primary biliary cirrhosis in 16 patients and type-1 autoimmune hepatitis in 8). The analytical liver profile was not useful in differentiating between viral and autoimmune liver disease. In contrast, patients with SS and autoimmune liver disease presented higher mean values of erythrocyte sedimentation rate (p = 0.044), circulating gammaglobulins (p = 0.007), and a higher prevalence of antinuclear antibodies (p < 0.001), antimitochondrial antibodies (p < 0.001), anti-smooth muscle antibodies (p = 0.026), anti-Ro/SSA (p < 0.001), and anti-La/SSB (p = 0.01), while patients with chronic viral liver disease had a higher frequency of cryoglobulinemia (p < 0.001) and hypocomplementemia (p < 0.001). CONCLUSION: Chronic viral liver disease (associated overwhelmingly with HCV) was the main cause of liver involvement in our patients with SS, with a prevalence of 13%, nearly 3-fold greater than that observed for autoimmune liver involvement. The immunological pattern played a key role in the differentiation of viral (predominance of cryoglobulins and low complement levels) and autoimmune (higher frequency of autoantibodies) liver involvement.

Autoantibodies↗
PubMed2005

Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats.

BACKGROUND/AIMS: Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats. METHODS: Rats with portal hypertension induced by partial portal vein ligation were treated with SU5416 or vehicle during 5 days. Then, hemodynamic studies were performed using radioactive microspheres. Protein expressions of CD31, VEGF receptor-2 and VEGF were also determined by Western blotting. RESULTS: Treatment of portal hypertensive rats with SU5416 resulted in a significant and marked decrease (by 44%) in portal venous inflow, and increases in splanchnic arteriolar resistance (by 68%) and portal venous resistance (by 93%). In addition, SU5416 administration significantly inhibited the formation of portal-systemic collateral vessels (52% inhibition), as well as the splanchnic CD31 and VEGF receptor-2 protein expressions in portal hypertensive rats, compared with those receiving vehicle. CONCLUSIONS: This study demonstrates that the development of hyperdynamic splanchnic circulation and the formation of portal-systemic collateral vessels in portal hypertensive rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of the VEGF signaling pathway. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.

Angiogenesis Inhibitors↗
PubMed2005

Ascites from cirrhotic patients induces angiogenesis through the phosphoinositide 3-kinase/Akt signaling pathway.

BACKGROUND/AIMS: Ascites in patients with cirrhosis is associated with worsening of systemic hemodynamics. Thus, the aim of this study was to investigate the biological activity of ascites on endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were used to investigate the angiogenic activity of ascites obtained from cirrhotic patients. RESULTS: Ascites-induced Akt activation, cell migration and tube formation in HUVECs. The pretreatment of HUVECs with the phosphatidylinositide 3-kinase (PI3-kinase) inhibitor LY294002, resulted in a decrease in chemotaxis and cell tube formation induced by ascites. Moreover, the inhibition of Akt activity in HUVECs by transduction of an inactive phosphorylation Akt mutant (AA-Akt), blocked tube formation. These angiogenic effects of ascites were also operative in vivo showing a PI3-kinase activation dependence in the angiogenesis induced by ascites. In addition, the preincubation of ascites with anti-fibronectin antibody led to a significant decrease in HUVECs migration, cell tube formation and in vivo angiogenesis. CONCLUSIONS: These results confirm the novel concept that ascites is a bioactive fluid which can modify vascular properties through the activation of the PI3-kinase/Akt pathway in endothelial cells. Furthermore, our results demonstrated that this ascites-induced mechanism is mediated, at least in part, by fibronectin.

Animals↗
PubMed2005

Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis.

BACKGROUND: Since primary biliary cirrhosis (PBC) is usually diagnosed in postmenopausal women with minor cholestasis, it has been questioned whether PBC itself represents a further risk for osteoporosis. AIM: To assess the prevalence and risk factors for osteoporosis in an unselected series of women with PBC. PATIENTS AND METHODS: 142 women with PBC (age: 54.3+/-0.8 years) and an age-matched control group. Osteoporosis was established by densitometry (bone mineral density below -2.5 T-score). Age, duration and severity of PBC, body mass index, menopausal status, histological stage and markers of bone turnover were assessed. RESULTS: Prevalence of osteoporosis was higher in PBC (32.4%) than in normal women (11. 1%) (RR: 3.83, 95%CI: 2.59-5.67, P<0.001). Osteoporosis was associated with older age, menopausal status, body mass index, longer PBC duration, advanced histological stage, high bilirubin and alkaline phosphatase, and low albumin and prothrombin index. Regression analysis identified older age, higher Mayo risk score, lower body mass index and advanced histological stage but not menopause as the independent risk factors for osteoporosis. CONCLUSIONS: Osteoporosis is more prevalent in women with PBC than in the general population. Age and severity of the disease, but not menopausal status, are the main risk factors for osteoporosis in this liver disease.

Biomarkers↗
PubMed2005

Nosocomial transmission of HCV in the liver unit of a tertiary care center.

Despite its medical and legal implications, there are no prospective studies analyzing the incidence and mechanisms involved in the nosocomial transmission of hepatitis C virus (HCV) in liver units. This study prospectively investigates the nosocomial transmission of HCV in the liver unit of a tertiary care center from August 2000 to October 2002. The median prevalence of HCV infection among hospitalized patients was 50%. Anti-HCV-negative patients admitted to the liver unit during the study period were prospectively followed, and serum markers of HCV infection were repeated 6 months after discharge. All known risk factors for HCV transmission (including the physical allocation of HCV-infected and noninfected patients during hospitalization) were recorded. Complete follow-up data were available in 1301 (84.5%) of 1540 patients. Six patients (0.46%) acquired HCV infection (annual incidence: 0.27/100 admissions). Phylogenetic analyses of recovered HCV sequences identified the source of infection as an HCV-infected roommate (3 cases) and a patient receiving care by the same nurse team (1 case). The most relevant risk factors associated with HCV acquisition were duration of hospitalization (>10 days; OR, 35; 95% CI, 1.96-622) and hospitalization with an HCV-infected roommate (>5 days; OR, 12; 95% CI, 1.39-103). In fact, HCV infection occurred in 1.7% of the 357 patients hospitalized longer than 10 days. In conclusion, HCV nosocomial infection appears to occur via patient-to-patient transmission in liver units, particularly in individuals who require long hospitalizations. Continuous reinforcement of universal prevention measures and, when possible, isolation of patients at higher risk might further reduce nosocomial HCV transmission.

Adolescent↗
PubMed2005

MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation.

Important progress has been made recently regarding the pathogenesis and treatment of hepatorenal syndrome (HRS). However, scant information exists about factors predicting outcome in patients with cirrhosis and HRS. Moreover, the prognostic value of the model of end-stage liver disease (MELD) score has not been validated in the setting of HRS. The current study was designed to assess the prognostic factors and outcome of patients with cirrhosis and HRS. The study included 105 consecutive patients with HRS. Forty-one patients had type 1 HRS, while 64 patients had type 2 HRS. Patients with type 1 HRS not only had more severe liver and renal failure than type 2 patients, they also had greater impairment of circulatory function, as indicated by lower arterial pressure and higher activation of vasoconstrictor factors. In the whole series, the median survival was 3.3 months. In a multivariate analysis of survival, only HRS type and MELD score were associated with an independent prognostic value. All patients with type 1 HRS had a high MELD score (> or =20) and showed an extremely poor outcome (median survival: 1 mo). By contrast, the survival of patients with type 2 HRS was longer and dependent on MELD score (> or =20, median survival 3 mo; <20, median survival 11 mo; P < .002). In conclusion, the outcome of patients with cirrhosis and HRS can be estimated by using two easily available variables, HRS type and MELD score. These data can be useful in the management of patients with HRS, particularly for patients who are candidates for liver transplantation.

Decision Support Techniques↗
PubMed2005

Hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a major complication of patients with cirrhosis, with the annual incidence in patients with ascites being approximately 8% []. This syndrome develops in the latest phase of the disease and there is now evidence that it is an important determinant of patient survival. Many aspects of HRS are, however, still poorly understood. There are two types of HRS: type 1 or progressive HRS which is associated with a very poor prognosis (median survival rate lower than 2 weeks), and type 2 HRS which is characterized by a steady impairment in circulatory and renal function. The pathogenesis of HRS is a deterioration in effective arterial blood volume due to splanchnic arterial vasodilation and a reduction in venous return and cardiac output. It is therefore not surprising that the syndrome can be reversed by the simultaneous intravenous administration of albumin and arterial vasoconstrictors. Intrarenal mechanisms are also important and require prolonged improvement in circulatory function to be deactivated. Long-term administration of intravenous albumin and vasoconstrictors or the correction of portal hypertension with a transjugular intrahepatic portacaval shunt are effective in the treatment of HRS. They also appear to improve survival and may serve as a bridge to liver transplantation, which is the treatment of choice in these patients.

Albumins↗
PubMed2005

Sustained aquaretic effect of the V2-AVP receptor antagonist, RWJ-351647, in cirrhotic rats with ascites and water retention.

1 A disturbance in body water homeostasis is a common feature in advanced cirrhosis. This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. Vasopressin (AVP) is of major importance in the pathogenesis of water retention and hyponatremia in cirrhosis. 2 The current study assessed the renal, hormonal and hemodynamic effects induced by 10-day chronic oral administration of RWJ-351647 (0.5 mg kg(-1) daily), a new nonpeptide V(2)-AVP antagonist, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. Urine volume (UV), urine osmolality and sodium and potassium excretion were measured daily. At the end of the study, systemic hemodynamic parameters were also assessed. 3 Long-term administration of RWJ-351647 has an aquaretic effect in rats with cirrhosis, ascites, water retention and hypo-osmolality. It increases UV (ANOVA: F=7.32, P<0.0001) and reduces urine osmolality (ANOVA: F=12.69, P<0.0001) throughout the entire period of treatment, thereby leading to a greater renal ability to excrete a water load at the end of the 10-day treatment period (the percentage of water load excreted improved from 30+/-8 to 92+/-21%, P<0.025). 4 The nonpeptide AVP V(2)-receptor antagonist RWJ-351647 also increased sodium excretion without affecting creatinine clearance and blood pressure. 5 These data suggest that RWJ-351647 could be therapeutically useful in the treatment of water retention in human cirrhosis.

Animals↗
PubMed2005

Microarray analysis of endothelial differentially expressed genes in liver of cirrhotic rats.

BACKGROUND & AIMS: There is a long-standing interest in the identification of endothelial-specific pathways for therapeutic targeting in cirrhosis. Therefore, the aim of this study was to evaluate differences in gene expression patterns between liver endothelial cells (LECs) from control and cirrhotic rats by using microarrays. METHODS: LECs were obtained by isopycnic centrifugation. LECs gene expression was then analyzed on high-density oligonucleotide microarrays. RESULTS: Analysis of gene expression revealed that most of the differentially expressed mRNA in cirrhosis are associated with extracellular matrix remodeling, inflammation, antioxidant/stress response, and cell signaling. CONCLUSIONS: The collective expression changes observed within some functional groups of genes indicate that LECs in cirrhotic livers may contribute to lymphangiogenesis, enhancement of fibrogenesis and inflammatory processes, changes in cell-cell interaction with up-regulation of adherens junction proteins, and alterations in the intrahepatic vascular tone because of the down-regulation of genes involved in vasodilatation.

Animals↗
PubMed2005

Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.

BACKGROUND & AIMS: Although renal failure is a common complication of sepsis and patients with cirrhosis frequently develop sepsis, there have been no studies specifically assessing renal function in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. The aim of this study was to investigate prospectively the frequency, characteristics, and outcome of renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. METHODS: One hundred six consecutive patients with cirrhosis and sepsis were studied prospectively. Patients with spontaneous bacterial peritonitis were excluded. RESULTS: Twenty-nine out of 106 patients (27%) with cirrhosis and sepsis developed acute renal failure as compared with only 8 of 100 patients (8%) from a control group of cirrhotic patients without infection (P < .0001). Renal failure in the sepsis group was reversible in 22 (76%; 21% of all patients) patients and nonreversible in 7 (24%; 6% of all patients) patients. Renal failure was associated with impairment of effective arterial blood volume, without evidence of tubular damage. The occurrence and type of renal failure correlated strongly with mortality (mortality at 3 months: nonreversible renal failure, 100%; reversible renal failure, 55%; no renal failure, 13%). Among variables obtained at diagnosis of sepsis, the Model for End-Stage Liver Disease (MELD) score was the only independent predictive factor of mortality. CONCLUSIONS: Renal failure is common in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis and is associated with arterial underfilling and renal vasoconstriction. Outcome is poor, even in the setting of reversible renal failure. The MELD score is the best prognostic marker of patients with cirrhosis and sepsis.

Adult↗
PubMed2005

Gene polymorphisms as predictors of decreased bone mineral density and osteoporosis in primary biliary cirrhosis.

Osteoporosis is a common complication observed in patients with primary biliary cirrhosis (PBC), with a prevalence of around 25%. The pathogenesis of bone loss in PBC is not well understood, since low bone formation and high resorption have been described. Bone disease is influenced by the duration and severity of the disease and oestrogen deficiency secondary to menopause. Genetic susceptibility has also been considered for osteoporosis in PBC, including vitamin D receptor genotypes, the gene encoding collagen type I alpha1 and insulin growth factor 1 gene microsatellite repeat polymorphism. Based on current evidence, the proposed genotypes either do not influence the development of osteoporosis in PBC or play only a minor role in it. The duration as well the severity of cholestasis are the main factors for such a disturbance since they are associated with the degree of bone loss. These features may exceed the potential effect of gene polymorphisms on osteoporosis in PBC.

Bone Density↗
PubMed2005

Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics.

BACKGROUND: Homocysteine (Hcy) is formed as an intermediary in methionine metabolism. Impairment of Hcy remethylation or transulfuration leads to hyperhomocysteinemia, which is considered as a risk factor for atherosclerotic vascular disease and stroke in chronic alcoholics. The aim of the study was to investigate the prevalence of hyperhomocysteinemia in chronic alcoholics and the influence of alcohol consumption, vitamin deficiencies and liver damage on the plasma levels of Hcy. METHODS: 228 chronic alcoholic patients consecutively admitted for detoxication, classified according to clinical and biochemical data in normal liver (n = 117), and in mild to moderate liver disease (n = 111), and 49 healthy controls were studied. Blood levels of Hcy, vitamin B6, vitamin B12 and folate were measured. RESULTS: Plasma Hcy was significantly higher in chronic alcoholics than in controls (9.66 +/- 8.1 vs. 6.93 +/- 2.33 mumol/liter, p < 0.025). Furthermore, plasma Hcy levels were significantly higher in chronic alcoholics with liver injury (12.17 +/- 10.14 mumol/liter) than in those with normal liver and in controls (p < 0.001). The prevalence of hyperhomocysteinemia was also significantly higher in alcoholics with liver damage than in those with normal liver and in controls (29.7%, 5.1%, and 2%, respectively, p < 0.001). Serum folate values were lower in chronic alcoholics than in controls (4.7 +/- 2.6 vs. 7.6 +/- 2.4 nmol/liter, p < 0.001). The lowest values of folate were found in alcoholics with liver disease, especially in those with hyperhomocysteinemia, with a negative correlation between the two parameters. CONCLUSIONS: Moderate hyperhomocysteinemia is common in chronic alcoholics, mainly in those with liver damage, suggesting that, although folate deficiencies may have a contributory role, liver impairment, through changes in methionine metabolism, is the most important mechanism for the elevated plasma Hcy found in these patients.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

Sinusoidal endothelial COX-1-derived prostanoids modulate the hepatic vascular tone of cirrhotic rat livers.

CCl(4) cirrhotic rat liver exhibits a hyperresponse to the alpha(1)-adrenergic agonist methoxamine (Mtx) that is associated with enhanced thromboxane A(2) (TXA(2)) production and is abrogated by indomethacin. To further elucidate the molecular mechanisms involved in the hyperresponse to vasoconstrictors, portal perfusion pressure dose-response curves to Mtx were performed in CCl(4) cirrhotic rats livers after preincubation with vehicle, the cyclooxygenase (COX)-1 selective inhibitor SC-560, and the COX-2 selective inhibitor SC-236. TXA(2) production was determined in samples of the perfusate. COX-1 expression was analyzed and quantified in hepatocytes, Kupffer cells, sinusoidal endothelial cells (SEC), and hepatic stellate cells (HSC) isolated from control and cirrhotic rat livers by double-immunofluorescence staining, with specific markers for each population using flow cytometry or Western blot analysis. COX-1 protein levels were not significantly increased in cirrhotic livers, but COX-2 protein expression was increased. COX-1 inhibition, but not COX-2, significantly attenuated the response to Mtx and prevented the increased production of TXA(2). Cirrhotic livers showed an increased expression of COX-1 in SEC and reduced expression in HSC compared with control livers, whereas COX-1 was similarly distributed in Kupffer cells. Despite abundant hepatic COX-2 expression, the increased response to Mtx of cirrhotic livers is mainly dependent of COX-1. Upregulation of COX-1 in cirrhotic SEC may be responsible for the hyperesponse to Mtx.

Animals↗