in melanoma cell motility and invasion during hepatic metasIn this work we report the presence of intrametastatic tasis progression. (HEPATOLOGY 1997;26:634-642.) smooth-muscle iso-alpha-actin (SMA)-expressing cells which appeared from the early stages of the hepatic metastasis process of intrasplenically injected B16 melanoma (B16M) cells.The prominent desmoplastic fibroblast stroma seen in maThey formed a network of stromal cells among B16M cells, lignant neoplasms and in their derived metastases suggests a very low percentage of them expressing desmin. In contrast, that tumor-infiltrating fibroblasts play a role in cancer prothose parts of liver tissue unaffected by metastasis had perisi-gression 1 and metastasis. [2][3][4] Such fibroblasts are tumor-innusoidal desmin-expressing quiescent hepatic stellate cells duced and differ in a number of functional aspects from their (qHSC) which did not express SMA. Exposure of freshly iso-resting precursors; thus, in most cases they are myofilated rat quiesent hepatic stellate cells (qHSC) to B16M cell-broblast-like cells 5 expressing specific surface and cytoskeleconditioned medium (B16M-CM) leads to a progressive in-tal markers. 4 Moreover, their role may involve the secretion crease (P õ .01) in the number of SMA-expressing cells, which of specific proteins such as cytokines, 6 extracellular matrix was accompanied by a parallel reduction in the number of molecules 7,8 and proteases, 9,10 and the contraction of the tudesmin-expressing cells. In addition, B16M-CM also con-mor matrix, thereby facilitating tumor development 5 and retained chemotactic factor(s) which significantly (P õ .01) ducing the involvement of immune cell responses. 1 However, increased (50%) in vitro qHSC migration and stimulated both despite this plethora of information, further insights into the [ 3 H]thymidine and [ 3 H]glucosamine uptake in qHSC. More-specific origins and phenotypic heterogeneity, as well as into over, B16M-CM also significantly (P õ .01) enhanced qHSC the regulation and role of these cells, are lacking because of secretion of matrix metalloproteinase-2 (MMP-2), and un-the numerous types of existing tumors and sites of developknown chemotactic factor(s) enhancing in vitro migration of ment. B16M cells. The results suggest that B16 melanoma releasesThe liver is one of the first sites of primary or secondary qHSC-activating factors, which induce the appearance of me-oncogenesis, and numerous reports have also described the tastasis-infiltrating myofibroblasts by a paracrine mechanism. development of hepatic fibroblasts as myofibroblast-like cells Such cells showed cytoskeletal alterations which are associ-concomitantly with hepatocellular carcinoma. 11,12 Not surated with enhanced proliferation, glycosaminoglycan synthe-prisingly, the hepatic fibroblast population surrounding sinusis, MMP-2 secretion, and tumor-chemotactic factor produc-soids, i.e., the Ito, fat-storing, or hepatic stellate cells (HSC), tion. Thus, tumor-activated qHSC may play an important role constitutes a qu...

Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6-174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL -1 ), followed by CG genotype (mean 1113 pg mL -1 ), and lowest in individuals with the CC genotype (mean 256 pg mL -1 ). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL -1 ) and patients with the IL6 CC genotype (555 pg mL -1 ) compared to patients with the -174 GG genotype (276 pg mL -1 ). In conclusion, the IL6-174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials.

OBJECTIVE -Retinol-binding protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and elevated serum RBP4 indicates overt or impending insulin resistance in lean, obese, and type 2 diabetic subjects. As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic liver disease (CLD).RESEARCH DESIGN AND METHODS -Serum RBP4 was measured in 111 CLD patients. Ninety-nine age-and sex-matched healthy blood donors served as control subjects. RBP4 gene expression was also quantified in normal and cirrhotic rat liver. RESULTS-In CLD patients, serum RBP4 was significantly reduced compared with healthy control subjects and closely correlated with the stage of liver cirrhosis. CLD patients without cirrhosis showed normal RBP4 concentrations, which correlated with serum glucose and insulin secretion and inversely correlated with insulin sensitivity. In patients with Child A-C liver cirrhosis, however, RBP4 was not correlated with glucose metabolism or other adipokines, such as adiponectin or resistin, but closely linked to the hepatic biosynthetic capacity, fibrotic changes in liver histology, or clinical complications such as portal hypertension. In an animal model of experimental cirrhosis, hepatic RBP4 gene expression decreased in cirrhotic liver.CONCLUSIONS -RBP4 appears, unlike in obesity or type 2 diabetes, not to be a relevant systemic factor in the pathogenesis of insulin resistance in liver cirrhosis. Liver function has a tremendous impact on RBP4 levels, and future studies will need to take liver function into account when examining serum RBP4 levels. Abbreviations: CLD, chronic liver disease; HOMA-S, homeostasis model assessment index; MELD, Model for End-Stage Liver Disease; RBP4, retinol-binding protein 4.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Summary:The time-dependent concentrations of hyaluronan, aminoterminal propeptide of type III procollagen, and laminin were determined in sera of 16 patients with severe adult respiratory distress syndrome during treatment with an extracorporeal CO 2 removal device. Patients were classified according to lung Parameters äs responders (n = 10) and non-responders (n = 6) to extracorporeal CO 2 removal. At the beginning of treatment strongly elevated serum concentrations of all studied extracellular matrix components were found. During the first 6-11 days of treatment the concentrations of aminoterminal propeptide of type III procollagen and hyaluronan increased further in non-responders but decreased in the majority of responders, while laminin decreased in both groups. No significant correlations were found between the serum concentrations of connective tissue components and the parameters of lung function. By non-parametric analysis of variance, significant differences between responders and non-responders according to treatment time could be established. By analysing the time course of the serum concentrations of hyaluronan and aminoterminal propeptide of type III procollagen, a total differentiation between responders and nonresponders was made pössible by the trends of these analytes äs early äs three days after the Start of treatment. The determination of aminoterminal propeptide of type III procollagen and hyaluronan in serum of patients with adult respiratory distress syndrome might therefore have prognostic significance in extracorporeal CO 2 removal. unfavourable rapid development of pulmonary fibroThe adult respiratory distress syndrome is a severe sis within about 2 weeks (5, 6), characterized by an condition of life-threatening organ failure, character-increase in fibroblast numbers and accelerated collaized by tachypnoea, hypoxaemia, diffuse interstitial gen metabolism (7,8). mfiltrates, alveolar oedema, and loss of lung compliance (l, 2). The syndrome develops in response to a Components of the extracellular matrix have been primary attack on lung cells like inhalation of toxins, determined in blood of patients with fibrotic lung aspiration of gastric contents (3) or äs a consequence diseases, but in contrast to e. g. liver fibrosis there of systemicdisorders like septicshock and multiorgan seems to be only a weak association between the trauma. Severe, progressive cases are associated with concentrations of such analytes in blood and the a mortality rate of up to 90% (4). One sequel of adult activity and/or grade of the fibrosing process in the respiratory distress syndrome is the prognostically lung (9).