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81.
Lopez AF; Dyson PG; To LB; Elliott MJ; Milton SE; Russell JA; Juttner CA; Yang YC; Clark SC; Vadas MA 《Blood》1988,72(5):1797-1804
Recombinant human (rh) interleukin-3 (IL-3) stimulated the proliferation and differentiation of erythroid, granulocyte, macrophage, eosinophil (Eo), and mixed colonies as well as megakaryocytes from human bone marrow cells. rh IL-3 was a weaker stimulus than rh granulocyte-macrophage colony-stimulating factor (GM- CSF) for day 14 myeloid cell colonies. At day 7 of incubation, rh IL-3 stimulated a few G, M, and Eo clusters but no colonies. This loss of responsiveness of myeloid cells to rh IL-3 was accentuated with further differentiation of the cells. rh IL-3 stimulated very few or no clones after five-day incubation with enriched promyelocytes and myelocytes, whereas rh GM-CSF was an efficient stimulus. Responsiveness to rh IL-3 was completely lost in postmitotic mature neutrophils. Incubation of these cells with rh IL-3 did not result in enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells or superoxide anion production after stimulation with formyl-methyl-leucyl-phenylalanine (FMLP), although they could be stimulated by rh GM-CSF. In addition, preincubation of neutrophils with different concentrations of rh IL-3 failed to increase or decrease their response to rh GM-CSF. In contrast to neutrophils, mature Eos could be stimulated by rh IL-3 to kill antibody-coated tumor cells. These results show that cells of the neutrophilic myeloid series lose their responsiveness to h IL-3 as they differentiate and suggest that although h IL-3 may be an important therapeutic agent to use for hematopoietic regeneration in vivo, the lack of stimulation of mature neutrophil function makes it an unlikely sole candidate as adjunct therapy for treatment of infectious diseases. 相似文献
82.
Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells 总被引:1,自引:0,他引:1
Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate- labeled receptors by purified neutrophil elastase produces 52- and 30- kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl- valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions. 相似文献
83.
Plasmic degradation of crosslinked fibrin has been studied to identify the proteolytic cleavages that convert the clot into a soluble lysate and also to identify the derivatives that are likely to circulate during clot dissolution. Initial polypeptide chain cleavages do not disrupt the solid clot matrix. With continued exposure to plasmin, high molecular weight derivatives are produced that remain attached to the clot by noncovalent forces. Further degradation then results in the liberation into solution of several large, noncovalently bound complexes. Progressive degradation of the largest, initially liberated complexes to the terminal derivatives, DD/E, DD, and E, occurs in solution after their release from the clot. As the fibrin clot is exposed to plasmin for longer intervals, progressive dissolution occurs, but the structure of the covalently bound insoluble fibrin core, the noncovalently attached derivatives, and the liberated complexes remains constant. Since much of the initially liberated protein is in complexes larger than DD/E, these derivatives probably represent the more prevalent plasmic degradation products of crosslinked fibrin in vivo. 相似文献
84.
The hematologic disorder paroxysmal nocturnal hemoglobinuria (PNH) occurs following an acquired somatic mutation in the Piga gene within a bone marrow stem cell. The progeny of this mutated cell cannot synthesize glycosylphosphatidylinositol (GPI) anchors, with a resultant deficiency in surface expression of all GPI-linked proteins. The protean clinical manifestations of PNH presumably result from the deficiency of these GPI-linked surface proteins. To explain the observation that neutrophils are affected at a significantly higher percentage than circulating erythrocytes and to analyze the proliferative rates of erythroid production in PNH, we studied 25 patients using flow cytometry. The fluorescent dye thiazole orange was used to detect reticulocytes, and CD59 monoclonal antibody was used to identify GPI-deficient cells. In contrast to the mature circulating erythrocytes, the percentage of abnormal reticulocytes was similar to the percentage of affected neutrophils. However, the vast majority of reticulocytes was completely GPI-deficient, ie, were type III cells, even in patients with only modest numbers of circulating type III erythrocytes. In addition, greater than 5% type II reticulocytes were identified in only 3 patients, although greater than 5% type II mature erythrocytes were identified in 10 of 25 patients. The results show that the erythroid and neutrophil bone marrow precursors have an equivalent proliferative advantage in PNH. The data also have important implications for the origin of type-II erythrocytes in PNH. 相似文献
85.
Thirty-two patients treated on consecutive Southwest Oncology Group (SWOG) protocols for malignant lymphoma were subsequently diagnosed as having lymphoblastic lymphoma. Combination chemistry, usually adriamycin-based, produced complete responses (CR) in 17 patients (53%). Median survival was 15 mo. Patients achieving a CR survival significantly longer than patients with partial or no response (p < 0.01). Ten of 24 patients not receiving central nervous system (CNS) prophylaxis developed leptomeningeal lymphoma while none of the seven patients who received prophylactic intrathecal cytosine arabinoside or methotrexate developed CNS lymphoma (p = 0.04). Implications of these results for planning future treatment programs of lymphoblastic lymphoma are discussed. 相似文献
86.
Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro 总被引:5,自引:3,他引:5
The recently cloned c-mpl ligand, thrombopoietin (Tpo), has been extensively characterized with regard to its ability to stimulate the growth, development, and ploidy of megakaryocyte progenitor cells and platelet production in vitro and in vivo. Primitive hematopoietic progenitors have been shown to express c-mpl, the receptor for Tpo. In the present study, we show that Tpo efficiently promotes the viability of a subpopulation of Lin-Sca-1+ bone marrow progenitor cells. The ability of Tpo to maintain viable Lin-Sca-1+ progenitors was comparable to that of granulocyte colony-stimulating factor and interleukin-1, whereas stem cell factor (SCF) promoted the viability of a higher number of Lin-Sca-1+ progenitor cells when incubated for 40 hours. However, after prolonged (> 40 hours) preincubation, the viability- promoting effect of Tpo was similar to that of SCF. An increased number of progenitors surviving in response to Tpo had megakaryocyte potential (37%), although almost all of the progenitors produced other myeloid cell lineages as well, suggesting that Tpo acts to promote the viability of multipotent progenitors. The ability of Tpo to promote viability of Lin-Sca-1+ progenitor cells was observed when cells were plated at a concentration of 1 cell per well in fetal calf serum- supplemented and serum-depleted medium. Finally, the DNA strand breakage elongation assay showed that Tpo inhibits apoptosis of Lin-Sca- 1+ bone marrow cells. Thus, Tpo has a potent ability to promote the viability and suppress apoptosis of primitive multipotent progenitor cells. 相似文献
87.
Tara L. Roberts Uda Ho John Luff C. Soon Lee Simon H. Apte Kelli P. A. MacDonald Liza J. Raggat Allison R. Pettit Carl A. Morrow Michael J. Waters Phil Chen Rick G. Woods Gethin P. Thomas Liam St. Pierre Camile S. Farah Raymond A. Clarke James A. L. Brown Martin F. Lavin 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(4):E285
SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development. 相似文献
88.
ObjectiveTo evaluate in vivo antioxidant and hepatoprotective activities of the methanolic extract of the root of Cassia singueana in rats following acute and chronic carbon tetrachloride intoxication.MethodsMalondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin as indices of liver damage and lipid peroxidation were detected in rats after intraperitoneal administration of extract (5 mg/kg).ResultsThe liver, kidney and heart showed significant reduction (P<0.05) in the levels of MDA from (0.18±0.04), (0.23±0.07) and (0.26±0.10) nmol/mg respectively in the CCl4 control to (0.15±0.03), (0.17±0.04) and (0.17±0.07) nmol/mg protein in groups pre-treated with the extract for three days at 5 mg/kg). Similarly, compared to the CCl4 control, significant reduction (P<0.05) in serum AST, ALT and bilirubin as well as in level of total cholesterol and MDA with concomitant increase in HDL cholesterol, superoxide dismutase and catalase levels when CCl4-intoxicated rats were treated with Cassia singueana root extract for two weeks.ConclusionsThese results suggest that methanolic extract of Cassia singueana contain potent antioxidant compounds that can offer significant protection against hepatic and oxidative injuries. 相似文献
89.
90.
Kinnison ML; Perler BA; Kaufman SL; Mitchell SE; Kadir S; Williams GM; White RI Jr 《Radiology》1986,160(3):727-730
In situ saphenous vein grafts are being used with increasing frequency for bypass procedures involving the femoral and popliteal arteries. Complications of these procedures include anastomotic stenoses and persistent arteriovenous fistulae that may result in failure of the graft. Balloon angioplasty and embolotherapy with detachable balloons were employed successfully in three or four recent cases of patients with complications from in situ grafts. Tailored angiography is essential for evaluating in situ grafts, and interventional techniques are extremely useful for managing complications. 相似文献