Plasma and hepatic tissue levels of thrombomodulin, tissue factor, NFκB and nitric oxide in responders and nonresponders to IFNα therapy

Abstract

Hepatitis C virus (HCV) infects hepatocytes and utilizes the hepatocyte to replicate. In so doing, many hepatocyte activities are shifted from their native state to one reflecting liver cell stress. Thrombomodulin and tissue factor are endothelial cell proteins that are expressed as a result of tissue injury or stress. Urokinase is a serine protease, which has been implicated in a number of physiologic and pathologic processes related to cellular stress and or injury. Nitric oxide is produced by cells in response to injury and functions both as a vasodilator and as an activator of a large number of cytokine cascades. NFkappaB is a transcription factor that forms one of the first lines of cellular defense against infection and hepatocellular stress. The levels of these four factors in plasma, hepatocyte cytosol and hepatocyte nuclear extracts provide a precise panoramic measure of cellular stress. Plasma, hepatocyte cytosol and nuclear extracts of hepatocytes were assayed for these four factors in 17 patients treated with alphaIFN for chronic hepatitis C. Five of the 17 were responders while 12 were nonresponders. Ten normal controls and 1 normal control liver were assayed also for each parameter. Nonresponders had 2x the plasma urokinase levels of responders and normals. The cytosol prepared from hepatocytes of nonresponders had a urokinase level 15-fold that of the controls and responders to IFN therapy. Plasma thrombomodulin levels in nonresponders were sixfold greater than those of responders and controls. The levels of all of the other measures in plasma, cytosol and nuclear extracts of liver tissue varied minimally between responders and nonresponders and the normal controls. These data demonstrate that: (i) urokinase levels in plasma and more clearly in cytosol are greater in nonresponders than responders, and (ii) plasma thrombomodulin levels in nonresponders are sixfold greater than those of responders and controls. These data suggest that urokinase and thrombomodulin may be unique markers of cellular and endothelial stress present in individuals with chronic hepatitis C. These markers might be useful during the clinical course of chronic hepatitis C, as a means of gauging the tissue response to therapy.

Single-stranded polyinosinic acid oligonucleotides trigger leukocyte production of proteins belonging to fibrinolytic and coagulation cascades

“…Following contact with mononuclear cells, dsRNA induces the expression of fibrinolytic protease precursor Plg, and it was not able to induce the expression of TF, a key activator of coagulation facilitating thrombus formation. These observations support previous reports about the extensive TF expression by mononuclear and endothelial cells infected by CMV, HSV [22], influenza virus, and hepatitis C [23]. To assess the role of nucleotides composing RNA strands for the expression of TF and Plg, preparations of RNA consisting of pure I, C, or U nucleotides were used.…”

“…This may by considered as a direct effect of RNA signaling through TLR or a secondary effect as a result of TNF-␣ or thrombin expression. In both cases, TF synthesis has been shown to be mediated through the NF-B signaling pathway [23,24].…”

Interferon-gamma–mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice

“…Mouse hepatitis virus infection is associated with intrahepatic thrombosis 27, 28. Patients with chronic hepatitis C show increase in plasma TF levels, whereas those with viral clearance by IFN‐α therapy, such as healthy controls, do not 29. Furthermore, there is a growing recognition of the role of hypercoagulation in chronic liver injury and fibrosis 30.…”

Assessment of plasma tissue factor activity in patients presenting with coronary artery disease: limitations of a commercial assay

“…In a subset of CAD patients, tTFp was lower than in normal subjects (Table S1; 58.5%-69.6%, P = 0.0001 CAD tTFp < 70%, n = 4 vs. healthy subjects (NL), n = 6), whereas in another patient subset, tTFp was higher than in normal subjects (233.6%-503.95%, P = 0.003 CAD tTFp > 130%, n = 8 vs. NL, n = 6); tTFp values of the healthy subjects (n = 6) were in the range of 75.2%-109.5% of normal pooled PPP. An outlier patient with the highest tTFp (503.95%) presented with hepatitis, which probably accounts for this extremely high tTFp, considering the activated state of the patientÕs immune system: very high levels of circulating TF antigen were recently reported in some patients with hepatitis C virus infection [7]. We also assessed the ACTI-FXa of each healthy subject and CAD patient.…”