15 research outputs found
Signal Transduction by the Chemokine Receptor CXCR3 ACTIVATION OF Ras/ERK, Src, AND PHOSPHATIDYLINOSITOL 3-KINASE/Akt CONTROLS CELL MIGRATION AND PROLIFERATION IN HUMAN VASCULAR PERICYTES
Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue-specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this study, we explored the signal transduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes. In HSC, interaction of CXCR3 with its ligands resulted in increased chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 also stimulated Src phosphorylation and kinase activity and increased the activity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. The increase in ERK activity was inhibited by genistein and PP1, but not by wortmannin, indicating that Src activation is necessary for the activation of the Ras/ERK pathway by CXCR3. Inhibition of ERK activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation resulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferation. These data characterize CXCR3 signaling in pericytes and clarify the relevance of downstream pathways in the modulation of different biologic responses
Pancreatic enzyme treatment in chronic pancreatitis : Quality of management and adherence to guidelines–A cross-sectional observational study
Objectives: Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence-based guidelines treatment of CP. Patients and methods: Patients with definitive or probable CP according to M-ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase <200 μg/g was defined as a marker for PEI. Enzyme replacement therapy of 100,000 lipase units or more was defined as adequate treatment. Results: We included 1006 patients from 8 centers in five countries. Sixty-four percent of the patients were correctly treated. Twenty-five per cent of PEI patients were not taking enzymes at all, and 20% of PEI patients were undertreated with insufficient PERT doses according to the guidelines. Fourteen percent of patients with sufficient pancreatic function were receiving enzymes despite normal exocrine pancreatic function. There were center differences. Current smoking was associated with lack of treatment and alcohol abuse was associated with under-treatment. There were no associations between “no treatment” or “under-treatment” for underweight or vitamin D deficiency. Conclusion: In our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence.publishedVersionPeer reviewe
Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells
Nuclear localization of TRK-A in liver cells
The liver represents a site of expression of
neurotrophins and their receptors. We have characterized
the expression and intracellular localization of the nerve
growth factor (NGF) receptor, Trk-A, in liver cells in
vivo and in vitro. In both normal and fibrotic liver tissue,
Trk-A immunostaining was present in different cell
types, including parenchymal cells and cells of the
inflammatory infiltrate. In hepatocytes and activated
stellate cells (HSC), Trk-A showed a predominant
nuclear localization, both in the presence and absence of
injury. In cultured HSC, Trk-A was found to be
functional, because exposure of the cells to recombinant
NGF resulted in stimulation of cell migration and
activation of intracellular signaling pathways, including
Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC,
Trk-A staining was found constitutively in the nucleus.
In these cells, Trk-A could be stained only by antibodies
directed against the intracellular domain but not by those
recognizing the extracellular portion of Trk-A
suggesting that the intracellular portion of the receptor is
the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not
show any nuclear localization of the intracellular portion
of Trk-A. In pheocromocytoma cells, nuclear staining
for Trk-A was not present in conditions of serum
deprivation, but could be induced by exposure to NGF or
to a mixture of soluble mediators. We conclude that
nuclear localization of the intracellular domain of Trk-A
is observed constitutively in liver cells such as HSC,
while in other cell types it could be induced in response
to soluble factors