Measurement of hepatic venous pressure gradient (HVPG) is a standard method for the assessment of portal pressure and correlates with the occurrence of its complications. Liver stiffness measurement (LSM) has been proposed as a noninvasive technique for the prediction of the complications of cirrhosis. In this study, we evaluated the ability of LSM to predict severe portal hypertension compared with that of HVPG in 61 consecutive patients with HCV-related chronic liver disease. A strong relationship between LSM and HVPG measurements was found in the overall population (r ‫؍‬ 0.81, P < 0.0001). However, although the correlation was excellent for HVPG values less than 10 or 12 mm Hg (r ‫؍‬ 0.81, P ‫؍‬ 0.0003 and r ‫؍‬ 0.91, P < 0.0001, respectively), linear regression analysis was not optimal for HVPG values >10 mm Hg (r 2 ‫؍‬ 0.35, P < 0.0001) or >12 mm Hg (r 2 ‫؍‬ 0.17, P ‫؍‬ 0.02). The AUROC for the prediction of HVPG >10 and >12 mm Hg were 0.99 and 0.92, respectively and at LSM cutoff values of 13.6 kPa and 17.6 kPa, sensitivity was 97% and 94%, respectively. In patients with cirrhosis, LSM positively correlated with the presence of esophageal varices (P ‫؍‬ 0.002), although no correlation between LSM and esophageal varices size was detected. The area under the ROC for the prediction of EV was 0.76 and at a LSM cutoff value of 17.6 kPa sensitivity was 90%. Conclusion: LSM represents a non-invasive tool for the identification of chronic liver disease patients with clinically significant or severe portal hypertension and could be employed for screening patients to be subjected to standard investigations including upper GI endoscopy and hemodynamic studies.

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Controlled degradation of extracellular matrix (ECM)1 is essential in physiological situations involving connective tissue remodeling, such as tissue morphogenesis, repair, and angiogenesis. On the other hand, excessive breakdown of connective tissue components plays an important role in destruction of functional tissue architecture, e.g. in rheumatoid arthritis, osteoarthritis, atherosclerosis, periodontitis, autoimmune blistering disorders of skin, and dermal photoaging as well as in invasion and metastasis of tumor cells (see Refs. 1-3). Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases collectively capable of degrading essentially all ECM components, and they are implicated in ECM remodeling in the physiologic and pathologic situations mentioned above. At present, 18 human members of the MMP family have been characterized, and most of them can be divided into subgroups of collagenases, gelatinases, stromelysins, and membrane-type MMPs based on their substrate specificity and structure (1-3).Collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13) are the principal neutral proteinases capable of degrading native fibrillar collagens in the extracellular space. They all cleave type I, II, and III collagens at a specific site, generating 3 ⁄4 N-terminal and 1 ⁄4 C-terminal fragments, which denature in physiological temperature and are further degraded by other MMPs, e.g. gelatinases (see Refs. 1-3). MMP-13 also cleaves type I collagen at N-terminal nonhelical telopeptide (4). MMP-1 cleaves type III collagen and MMP-8 type I collagen most effectively (1-3). MMP-13, in turn, cleaves fibrillar collagens with preference to type II collagen over type I and III collagens and displays 40-fold stronger gelatinase activity than MMP-1 and MMP-8 (5-7). In addition, MMP-13 degrades type IV, X, and XIV collagens, tenascin, fibronectin, and aggrecan core protein (8 -9). Apparently due to its exceptionally wide substrate specificity, the physiologic expression of MMP-13 is limited to situations in which rapid and effective remodeling of collagenous ECM takes place, i.e. fetal bone development and adult bone remodeling (10, 11). On the other hand, MMP-13 is expressed at sites of excessive degradation of

Endothelin-1 (ET-1) induces cell proliferation and differentiation through multiple G-protein-linked signaling systems, including p21 ras activation. Whereas p21 ras activation and desensitization by receptor tyrosine kinases have been extensively investigated, the kinetics of p21 ras activation induced by engagement of G-protein-coupled receptors remains to be fully elucidated. In the present study we show that ET-1 induces a biphasic activation of p21 ras in rat glomerular mesangial cells. The first peak of activation of p21 ras , at 2-5 min, is mediated by immediate association of phosphorylated Shc with the guanosine exchange factor Sos1 via the adaptor protein Grb2. This initial activation of p21 ras results in activation of the extracellular signal-regulated kinase (ERK) cascade. We demonstrate that ET-1 signaling elicits a negative feedback mechanism, modulating p21 ras activity through ERKdependent Sos1 phosphorylation, findings which were confirmed using an adenovirus MEK construct. Subsequent to p21 ras and ERK deactivation, Sos1 reverts to the non-phosphorylated condition, enabling it to bind again to the Grb2/Shc complex, which is stabilized by persistent Shc phosphorylation. However, the resulting secondary activation of p21 ras at 30 min does not lead to ERK activation, correlating with intensive, ET-1-induced expression of MAP kinase phosphatase-1, but does result in increased p21 ras -associated phosphatidylinositol 3-kinase activity. Our data provide evidence that ET-1-induced biphasic p21 ras activation causes sequential stimulation of divergent downstream signaling pathways.