interleukin-8 and marimastat

The extracellular matrix (ECM) creates the microenvironment of the tissue; an altered ECM in the asthmatic airway may be central in airway inflammation and remodelling. Tumstatin is a collagen IV-derived matrikine reduced in the asthmatic airway wall that reverses airway inflammation and remodelling in small and large animal models of asthma. This study hypothesized that the mechanisms underlying the broad asthma-resolving effects of tumstatin were due to autocrine remodelling of the ECM. Neutrophils and endothelial cells were seeded on decellularized ECM of non-asthmatic (NA) or asthmatic (A) airway smooth muscle (ASM) cells previously exposed to tumstatin in the presence or absence of a broad matrix metalloproteinase inhibitor, Marimastat. Gene expression in NA and A ASM induced by tumstatin was assessed using RT-PCR arrays. The presence of tumstatin during ECM deposition affected neutrophil and endothelial cell properties on both NA and A ASM-derived matrices and this was only partly due to MMP activity. Gene expression patterns in response to tumstatin in NA and A ASM cells were different. Tumstatin may foster an anti-inflammatory and anti-angiogenic microenvironment by modifying ASM-derived ECM. Further work is required to examine whether restoring tumstatin levels in the asthmatic airway represents a potential novel therapeutic approach.

Topics: Airway Remodeling; Angiogenesis Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Autoantigens; Bronchi; Chemotaxis; Collagen Type IV; Enzyme Inhibitors; Extracellular Matrix; Gene Expression Profiling; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Hydroxamic Acids; Interleukin-8; Matrix Metalloproteinases; Myocytes, Smooth Muscle; Neutrophils

MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down-regulation and its possible implications for glioma therapy in humans remain unclear, we observed a significant improvement in animal survival upon down-regulation of MMP14 in murine intracranial glioma xenografts infected with MMP14 shRNA-expressing CRAd. We further found that down-regulation of MMP14 in gliomas by combinational treatment with CRAd-S-5/3 and Marimastat, a chemical inhibitor of metalloproteinases, augments suppression of pro-angiogenic factors, caused by the replication-competent adenovirus. We also demonstrated that delivery of MMP14-targeting shRNA by a fiber-modified adenoviral vector to the glioma cells effectively suppresses their proliferation in vitro and in vivo. Thus our data indicate that inhibition of MMP14 expression in tumors in combination with glioma virotherapy could be effectively utilized to suppress angiogenesis and neovascularization of glioma tumors by decreasing production of pro-angiogenic factors.

Topics: Adenoviridae; Aged; Animals; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Genetic Therapy; Genetic Vectors; Glioma; Humans; Hydroxamic Acids; Interleukin-8; Male; Matrix Metalloproteinase 14; Mice; Middle Aged; Neoplasm Transplantation; Neovascularization, Pathologic; Oncolytic Virotherapy; RNA Interference; RNA, Small Interfering; Transplantation, Heterologous; Vascular Endothelial Growth Factor A