Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intraepithelial lymphocyte migration is a biological process frequently observed in skin and tonsil. Using immunohistochemistry, we have studied the molecular bases of this process in seven skin biopsies involved by mycosis fungoides (MF) and in 12 tonsils, four involved by B-chronic lymphocytic leukaemia (B-CLL) and eight by lymphoid follicular hyperplasia (LH). In the skin, intraepidermal T-lymphocyte infiltration was associated with narrowing and fragmentation of the basement membrane, as shown by an anti-collagen type IV antibody. Immunostaining of serial sections with an anti-collagenase type IV antibody revealed that collagenase type IV was localized in the upper dermis and strictly co-distributed with collagen type IV, suggesting that enzymatic digestion played a role in the alterations of the basement membrane. Further migration through the epidermis was mediated by expression on keratinocytes of intercellular adhesion molecule-1 (ICAM-1) and of leukocyte-function associated antigen-1 (LFA-1) on infiltrating lymphocytes. In the tonsil, intraepithelial infiltration was mediated by the expression of vascular cell adhesion molecule-1 (VCAM-1) by epithelial cells and of very late antigen-4 (VLA-4) by infiltrating lymphocytes. Further intraepithelial lymphocyte migration was then established, as already shown in the skin, by ICAM-1/LFA-1 interaction. Lymphocyte recruitment from the systemic circulation was studied using antibodies directed against endothelial leukocyte adhesion molecule-1 (ELAM-1), ICAM-1, and VCAM-1. These adhesion molecules were highly expressed by blood vessels in the upper dermis of MF and the percentage of ELAM-1+/VCAM-1+ vessels was significantly higher than that observed in tonsils.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular mechanisms involved in intraepithelial lymphocyte migration: a comparative study in skin and tonsil. 768 77

Monocytes have been shown to infiltrate in brain tissue during various neurological disorders including AIDS dementia complex. The presence of an excess of activated macrophages in brain tissue is accompanied by tissue damage resulting in a loss in neuronal function and viability. Therapeutic options against such neurological disorders could therefore be aimed at the prevention of monocyte infiltration across the blood - brain barrier. Therefore, a better understanding of these processes is needed. Recent insights in cellular processes between monocytes/macrophages and brain microvascular endothelial cells in the neuropathogenesis of HIV-1 infection demonstrate that monocytes roll on endothelial cells via the inducible endothelial adhesion molecule E-selectin. Binding of these cells are mainly mediated via the endothelial adhesion molecule vascular cell adhesion molecule-1. The transmigration through the blood - brain barrier is facilitated by both endothelial and monocyte/macrophage-derived nitric oxide and by the increased production of gelatinase B activity by HIV-infected monocytes/macrophages. Chemokines produced within the brain regulate the traffic of the infiltrating monocytes through the brain parenchyma. In addition, endothelial cells also produce monocyte attracting chemokines during their first interactions with HIV-infected monocytes/macrophages thus promoting additional influx of phagocytes into the brain. Furthermore, excessive infiltration of monocytes is accompanied by endothelial damage resulting in the loss of tight junctions. Thus, in toto, brain microvascular endothelial cells might contribute to the neuropathogenesis of HIV-1 infection.
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PMID:Interactions between macrophages and brain microvascular endothelial cells: role in pathogenesis of HIV-1 infection and blood - brain barrier function. 1060 6

Integrin alpha(4)beta(1) on the surface of T lymphocytes interacts with vascular cell adhesion molecule-1 (VCAM-1) and fibronectin during migration of lymphocytes from the blood to sites of inflammation. Migrating lymphocytes actively modify their environment through a number of mechanisms including proteolysis of the extracellular matrix by matrix metalloproteinases (MMP) synthesized by the cells. In this study, expression of MMP upon alpha(4)beta(1)-mediated adhesion of leukocytes to two major ligands, the IIICS-1 domain of fibronectin and VCAM-1, has been examined. Adhesion of T lymphoblastoid Jurkat cells to the CS-1 peptide induced expression of mRNA for two MMPs, gelatinase A (MMP-2) and gelatinase B (MMP-9). As evaluated by relative RT-PCR and Northern blot analyses, the level of mRNA was upregulated about 4- to 5-fold for both MMPs compared to control cells maintained in suspension. With time, both enzymes were detected in conditioned media and inside the cells, and their identities were verified by Western blotting and gelatin zymography. Adhesion of Jurkat cells to the second major alpha(4)beta(1) ligand, VCAM-1, upregulated mRNA for MMP-2 (3.5-fold) and failed to induce expression of mRNA for MMP-9. Accordingly, only MMP-2 protein was detected in conditioned media of cells adherent to VCAM-1. Occupancy of alpha(4)beta(1) on the surface of suspended cells with soluble CS-1 peptide or VCAM-1 did not upregulate synthesis and release of MMPs. A similar pattern of induction of MMPs after adhesion to CS-1 and VCAM-1 was observed in T lymphocytes isolated from human blood. These results demonstrate that adhesion of T lymphocytes through alpha(4)beta(1) to different ligands, which bind to similar or overlapping sites in the integrin, induces intracellular events leading to distinct patterns of MMPs biosynthesis.
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PMID:Differential induction of gelatinase B (MMP-9) and gelatinase A (MMP-2) in T lymphocytes upon alpha(4)beta(1)-mediated adhesion to VCAM-1 and the CS-1 peptide of fibronectin. 1101 Aug 12

Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34(+) cells in the peripheral blood (PB). We explored the possible mechanisms underlying this abnormal trafficking of CD34(+) cells. Plasma levels of neutrophil elastase (NE), total and active matrix metalloproteinase 9 (MMP-9), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were dramatically increased in IM. The absolute number of CD34(+) cells in the PB was correlated with the levels of sVCAM-1. Marked elevations of the levels of NE but not total and active MMP-9 as well as MMP-2 were detected in media conditioned by IM mononuclear cells (MNCs) as compared with that of healthy volunteers. IM MNC-conditioned media, however, was shown by zymographic analysis to contain increased gelatinolytic activity corresponding to the molecular weight of MMP-9. IM MNC-conditioned media also exhibited a greater ability to cleave VCAM-1 and c-kit in vitro, consistent with the biologic actions of NE. In addition, the increased ability of IM PB CD34(+) cells to migrate through a reconstituted basement membrane was diminished by several inhibitors of MMP-9 activity, indicating that these cells express increased levels of this MMP. These data indicate that a proteolytic environment exists in IM which might result in the sustained mobilization of CD34(+) cells.
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PMID:Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases. 1570 94

Mesenchymal stem cells (MSCs) can contribute to tissue repair by actively migrating to sites of tissue injury. However, the cellular and molecular mechanisms of MSC recruitment are largely unknown. The nuclear factor (NF)-kappaB pathway plays a pivotal role in regulating genes that influence cell migration, cell differentiation, inflammation, and proliferation. One of the major cytokines released at sites of injury is tumor necrosis factor-alpha (TNF-alpha), which is known to be a key regulator of the NF-kappaB pathway. Therefore, we hypothesized that TNF-alpha may lead to MSC invasion and proliferation by activation of the NF-kappaB pathway. TNF-receptor 1 and 2, NF-kappaB (p65), and IkappaB kinase 2 (IKK-2) are expressed in human MSCs (hMSCs). Stimulation of hMSCs with TNF-alpha caused a p65 translocation from the cytoplasm to nucleoplasm but did not change the expression profile of MSC markers. TNF-alpha strongly augmented the migration of hMSCs through the human extracellular matrix. Using lentiviral gene transfer, overexpressing a dominant-negative mutant of IKK-2 (dn-IKK-2) significantly blocked this effect. NF-kappaB target genes associated with migration (vascular cell adhesion molecule-1, CD44, and matrix metalloproteinase 9) were upregulated by TNF-alpha stimulation and blocked by dn-IKK-2. Moreover, using the bromodeoxyuridine assay, we showed that the inhibition of the NF-kappaB pathway caused a significant reduction in the basal proliferation rate. TNF-alpha stimulated the proliferation of hMSCs, whereas overexpression of dn-IKK-2 significantly blocked this effect. TNF-alpha led to the upregulated expression of the proliferation-associated gene cyclin D1. In conclusion, we demonstrated that the NF-kappaB pathway components, p65 and IKK-2, are expressed in hMSCs. Our data provide evidence that this signal transduction pathway is implicated in TNF-alpha-mediated invasion and proliferation of hMSCs. Therefore, hMSC recruitment to sites of tissue injury may, at least in part, be regulated by the NF-kappaB signal transduction pathway.
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PMID:IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. 1860 Mar 6

Posttraumatic inflammation and excessive neutrophil activation cause multiple organ dysfunction syndrome (MODS), a major cause of death among hemorrhagic shock patients. Traditional resuscitation strategies may exacerbate inflammation; thus, novel fluid treatments are needed to reduce such posttraumatic complications. Hypertonic resuscitation fluids inhibit inflammation and reduce MODS in animal models. Here we studied the anti-inflammatory efficacy of hypertonic fluids in a controlled clinical trial. Trauma patients in hypovolemic shock were resuscitated in a prehospital setting with 250 mL of either 7.5% hypertonic saline (HS; n = 9), 7.5% hypertonic saline + 6% dextran 70 (HSD; n = 8), or 0.9% normal saline (NS; n = 17). Blood samples were collected on hospital admission and 12 and 24 h after resuscitation. Multicolor flow cytometry was used to quantify neutrophil expression of cell-surface activation/adhesion (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers as well as oxidative burst activity. Circulating concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVACM-1), P- and E-selectins, myeloperoxidase (MPO), and matrix metalloproteinase 9 (MMP-9) were assessed by immunoassay. Multiple organ dysfunction syndrome, leukocytosis, and mortality were lower in the HS and HSD groups than in the NS group. However, these differences were not statistically significant. Hypertonic saline prevented priming and activation and neutrophil oxidative burst and CD11b and CD66b expression. Hypertonic saline also reduced circulating markers of neutrophil degranulation (MPO and MMP-9) and endothelial cell activation (sICAM-1, sVCAM-1, soluble E-selectin, and soluble P-selectin). Hypertonic saline + 6% dextran 70 was less capable than HS of suppressing the upregulation of most of these activation markers. This study demonstrates that initial resuscitation with HS, but neither NS nor HSD, can attenuate posttraumatic neutrophil and endothelial cell activation in hemorrhagic shock patients. These data suggest that hypertonic resuscitation without dextran may inhibit posttraumatic inflammation. However, despite this effect, neither HS nor HSD reduced MODS in trauma patients with hemorrhagic shock.
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PMID:Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation. 2277 13

Stem cell mobilization plays important roles in the treatment of severe ischemic diseases, including myocardial infarction, limb ischemia, ischemic stroke, and acute kidney injury. Stem cell mobilization refers to the egress of heterogeneous stem cells residing in the bone marrow into the peripheral blood. In the clinic, granulocyte colony-stimulating factor (G-CSF) is the drug most commonly used to induce stem cell mobilization. Plerixafor, a direct antagonist of CXCR4, is also frequently used alone or in combination with G-CSF to mobilize stem cells. The molecular mechanisms by which G-CSF induces stem cell mobilization are well characterized. Briefly, G-CSF activates neutrophils in the bone marrow, which then release proteolytic enzymes, such as neutrophil elastase, cathepsin G, and matrix metalloproteinase 9, which cleave a variety of molecules responsible for stem cell retention in the bone marrow, including CXCL12, VCAM-1, and SCF. Subsequently, stem cells are released from the bone marrow into the peripheral blood. The released stem cells can be collected and used in autologous or allogeneic transplantation. To identify better conditions for stem cell mobilization in the treatment of acute and chronic ischemic diseases, several preclinical and clinical studies have been conducted over the past decade on various mobilizing agents. In this paper, we are going to review methods that induce mobilization of stem cells from the bone marrow and introduce the application of stem cell mobilization to therapy of ischemic diseases.
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PMID:Role of stem cell mobilization in the treatment of ischemic diseases. 3068 May 45