The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury.

Liver fibrosis is a progressive pathological process involving inflammation and extracellular matrix deposition. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein and serine protease. DPP4 binds to fibronectin, can inactivate specific chemokines, incretin hormone and neuropeptides, and influences cell adhesion and migration. Such properties suggest a pro-fibrotic role for this peptidase but this hypothesis needs in vivo examination. Experimental liver injury was induced with carbon tetrachloride (CCl4) in DPP4 gene knockout (gko) mice. DPP4 gko had less liver fibrosis and inflammation and fewer B cell clusters than wild type mice in the fibrosis model. DPP4 inhibitor-treated mice also developed less liver fibrosis. DNA microarray and PCR showed that many immunoglobulin (Ig) genes and some metabolism-associated transcripts were differentially expressed in the gko strain compared with wild type. CCl4-treated DPP4 gko livers had more IgM+ and IgG+ intrahepatic lymphocytes, and fewer CD4+, IgD+ and CD21+ intrahepatic lymphocytes. These data suggest that DPP4 is pro-fibrotic in CCl4-induced liver fibrosis and that the mechanisms of DPP4 pro-fibrotic action include energy metabolism, B cells, NK cells and CD4+ cells.

Survival outcomes of a salvage patient population after radioembolization of hepatic metastases with yttrium-90 microspheres.

PURPOSE: To determine in a retrospective study the potential benefit on survival outcomes of radioembolization using yttrium-90 ((90)Y) resin microspheres in a cohort of patients presenting with chemotherapy-refractory liver metastases, primarily from colorectal cancer (CRC). MATERIALS AND METHODS: Over 3 years, 249 patients were referred to the authors' center to determine suitability for radioembolization as treatment for hepatic metastases. All patients were defined as salvage, having failed first-line and second-line chemotherapies. These patients were divided into group 1 (CRC) and group 2 (all other cancers, eg, breast, neuroendocrine) and assessed for overall survival (OS) as a whole and according to group. RESULTS: Using (90)Y resin microspheres, 208 patients were treated, undergoing 223 radioembolization treatments. The median OS was 8.3 months for the whole cohort, 7.9 months for group 1, and 8.7 months for group 2. At the 3-month follow-up, there was an overall adverse event rate of 9%. At the end of the data collection period, 62 patients were still alive. CONCLUSIONS: Radioembolization shows promise as an effective and safe treatment for patients with chemotherapy-refractory hepatic metastases providing an extension to survival in the salvage setting.

The in vivo expression of dipeptidyl peptidases 8 and 9.

The dipeptidyl peptidase IV (DPIV) enzyme family contains both potential and proven therapeutic targets. Recent reports indicate the presence of DP8 and DP9 in peripheral blood lymphocytes, testis, lung, and brain. For a more comprehensive understanding of DP8 and DP9 tissue and cellular expression, mRNA and enzyme activity were examined. Many organs from C57BL/6 wild-type and DPIV gene-knockout mice were examined; DP8/9 enzyme activity was detected in the immune system, brain, testis, muscle, and epithelia. In situ hybridization localized DP8 and DP9 mRNA to lymphocytes and epithelial cells in liver, gastrointestinal tract, lymph node, spleen, and lung. DP8 and DP9 mRNA was detected in baboon and mouse testis, and DP9 expression was elevated in human testicular cancers. DP8 and DP9 mRNA were ubiquitous in day 17 mouse embryo, with greatest expression in epithelium (skin and gastrointestinal tract) and brain. Thus, DP8 and DP9 are widely expressed enzymes. Their expression in lymphocytes and epithelia indicates potential for roles in the digestive and immune systems. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.