Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using anti-glomerular basement membrane nephritis in rats, we investigated the mechanisms underlying in situ chemokine expression and the in vivo function of these cytokines during the acute phase of this model. We observed that CXC chemokine expression was monophasic and paralleled neutrophil (PMN) influx, whereas CC chemokine expression was biphasic with peaks coinciding with the influx of PMNs and macrophages (Mphi). The initial peak of chemokine expression was attenuated by decomplementation, neutropenia, and leukopenia, while the latter peak was attenuated only by leukopenia and augmented in the accelerated form of this disease model, corresponding to an increase in Mphi influx. Differential expression of chemokines by PMNs and Mphi was not an intrinsic property of these cells, as these leukocytes expressed similar profiles of chemokines in vitro. Immunostaining for Mphi inflammatory protein-1alpha, a CC chemokine, in acute nephritis validated that expression during acute nephritis was accompanied by local protein production. Moreover, neutralizing Ab to Mphi inflammatory protein-1alpha attenuated the acute phase proteinuria, but not the accompanying influx of PMNs. Neutralizing Ab to cytokine-induced neutrophil chemoattractant (a CXC chemokine), in comparison, inhibited both PMN influx and proteinuria. A combination of both Abs was not significantly more effective than either alone. In sum, the influx of myeloid cells is necessary for local chemokine expression in anti-glomerular basement membrane nephritis, although the differential expression of CXC and CC chemokines must involve additional factors. CXC and CC chemokines also mediate distinct, but overlapping, pathophysiologic roles in the acute phase of this model.
 ...
PMID:Chemokines are expressed in a myeloid cell-dependent fashion and mediate distinct functions in immune complex glomerulonephritis in rat. 910 62

To test the hypothesis that low numbers of circulating neutrophils may be due to enhanced neutrophil extravasation in patients with chronic idiopathic neutropenia of adults (CINA), serum levels of endothelial cell-derived soluble cell adhesion molecules (sE-selectin, sICAM and sVCAM) usually used as indicators of endothelial cell activation, serum levels of two potent endothelial cell activators (IL-1beta and TNF-alpha), and serum levels of the chemokine interleukin-8 (IL-8) which is one of the main chemoattractant substances for neutrophils at sites of inflammation, were measured in 84 CINA patients and 30 healthy volunteers using the respective micro-ELISA methods. We found that serum sE-selectin, sICAM, sVCAM, IL-1beta and TNF-alpha concentrations were all significantly increased in the group of patients compared to controls, and were correlated inversely with the number of circulating neutrophils. Serum levels of IL-8 were also markedly increased in the patients compared to controls, and they were correlated positively with the levels of serum sE-selectin, sICAM, sVCAM, IL-1beta and TNF-alpha, and inversely with the number of circulating neutrophils. No significant differences were noted between patients and normal controls in the proportions of neutrophils carrying the cell adhesion molecules CD11a/ CD18, CD15 and CD62L. These findings suggest strongly that CINA patients have activated endothelium to which circulating neutrophils may adhere by interacting with counter-structures found on their surface. Subsequent diapedesis and subendothelial migration may be facilitated by IL-8 and possibly other chemoattractant substances. We conclude that an enhanced neutrophil extravasation may be involved, at least in part, in the determination of neutropenia in CINA patients.
 ...
PMID:Enhanced neutrophil extravasation may be a contributing factor in the determination of neutropenia in patients with chronic idiopathic neutropenia of adults. 982 Jun 35

The present study was designed to investigate the hypothesis that selective loss of peripheral blood CD45RO+ T lymphocytes in patients with chronic idiopathic neutropenia of adults (CINA), previously reported from our laboratory, may be due to enhanced extravasation into the tissues. Serum levels of endothelial cell-derived soluble cell adhesion molecules (sELAM, sICAM and sVCAM), usually used as indicators of endothelial cell activation, were measured in 73 CINA patients and 32 healthy volunteers using a micro-ELISA method. We found that patients had markedly elevated concentrations of all three soluble cell adhesion molecules studied compared to the controls, and serum levels of sELAM, sICAM and, more importantly, sVCAM correlated inversely with the numbers of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. Using a micro-ELISA method, we also measured serum levels of two endothelial cell activators, interleukin (IL)-1beta and TNF-alpha, and found that CINA patients had significantly higher cytokine concentrations than control subjects. Serum levels of IL-1beta and TNF-alpha correlated positively with the values of all three soluble cell adhesion molecules and inversely with the numbers of CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. Moreover, we measured serum levels of the chemokine RANTES by a micro-ELISA technique and found that CINA patients also had elevated concentrations of the molecule compared to controls. Serum RANTES correlated positively with IL-1beta, TNF-alpha, sICAM, sVCAM and sELAM and inversely with the numbers of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets. These findings strongly suggest that CINA patients have an activated endothelium to which CD45RA+ and CD45RO+ T cells tether and roll, but firm adhesion and transendothelial migration are restricted to CD45RO+ T cell subsets, as endothelial VCAM-1 interacts with the vascular leukocyte adhesion molecule-4 (VLA-4) constitutively expressed on CD45RO+ but not on CD45RA+ T cells. Subsequent subendothelial and tissue migration of CD45RO+ T cells may be facilitated by the chemokine RANTES, which acts mainly on CD45RO+ T cells. We concluded that selective loss of peripheral blood CD45RO+ T lymphocytes in CINA patients is probably due, at least in part, to enhanced extravasation of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets into the tissues.
 ...
PMID:Selective loss of peripheral blood CD45RO+ T lymphocytes correlates with increased levels of serum cytokines and endothelial cell-derived soluble cell adhesion molecules in patients with chronic idiopathic neutropenia of adults. 982 46

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that is widely used to treat neutropenia. In addition to stimulating polymorphonuclear neutrophil (PMN) production, G-CSF may have significant effects on PMN function. Because G-CSF receptor (G-CSFR)-deficient mice do not have the expected neutrophilia after administration of human interleukin-8 (IL-8), we examined the effect of the loss of G-CSFR on IL-8-stimulated PMN function. Compared with wild-type PMNs, PMNs isolated from G-CSFR-deficient mice demonstrated markedly decreased chemotaxis to IL-8. PMN emigration into the skin of G-CSFR-deficient mice in response to IL-8 was also impaired. Significant chemotaxis defects were also seen in response to N-formyl-methionyl-leucyl-phenylalanine, zymosan-activated serum, or macrophage inflammatory protein-2. The defective chemotactic response to IL-8 does not appear to be due to impaired chemoattractant receptor function, as the number of IL-8 receptors and chemoattractant-induced calcium influx, actin polymerization, and release of gelatinase B were comparable to those of wild-type PMNs. Chemoattractant-induced adhesion of G-CSFR-deficient PMNs was significantly impaired, suggesting a defect in beta2-integrin activation. Collectively, these data demonstrate that selective defects in PMN activation are present in G-CSFR-deficient mice and indicate that G-CSF plays an important role in regulating PMN chemokine responsiveness.
 ...
PMID:A functional granulocyte colony-stimulating factor receptor is required for normal chemoattractant-induced neutrophil activation. 1007 3

Acute thermal trauma is well known to produce evidence of a "systemic inflammatory response" in vivo, as manifested by evidence of complement activation, appearance in plasma of a variety of inflammatory factors, and development of multi-organ injury. The current studies were focused on acute thermal injury of rat skin and factors responsible for accompanying activation of blood neutrophils. Acute thermal injury of rat skin resulted in a time-dependent loss of L-selectin and up-regulation of Mac-1 (CD11b/CD18) on blood neutrophils, with no changes in LFA-1 (CD11a/CD18). The loss of L-selectin was prevented by blockade of C5a but not by blockade of the alpha-chemokine, macrophage inflammatory protein-2 (MIP-2). C5a, the alpha chemokines, MIP-2 and keratinocyte-derived cytokine (KC), and platelet activating factor (PAF) contributed to up-regulation of blood neutrophil Mac-1. Blocking interventions against these mediators also blunted the degree of neutropenia developing after thermal trauma. These data suggest that activation of blood neutrophils after thermal trauma is related to the role of several chemotactic mediators. These studies may provide clues regarding factors responsible for development of the "systemic inflammatory response syndrome" after thermal injury in the experimental model employed.
 ...
PMID:Role of chemotactic factors in neutrophil activation after thermal injury in rats. 1044 99

The chemokine interleukin-8 (IL-8) is a potent chemoattractant and activator of neutrophils. Upon systemic injection, IL-8 induces an immediate neutropenia followed by a rebound granulocytosis. In this report, we discuss the effects of IL-8 on the mobilization of hematopoietic stem cells. Within 20 minutes following a single intraperitoneal injection in mice, IL-8 induces the mobilization of hematopoietic progenitor cells (HPC) with colony-forming, radioprotective, and long-term lymphomyeloid resubpopulating ability. Mobilization can be specifically prevented by pretreatment with antibodies against the beta2 integrin LFA-1 (CD11a). In monkeys, IL-8 Induces the rapid release of the metalloproteinase gelatinase-B concurrent with the mobilization of HPC. The latter effect can be prevented by blocking gelatinase-B activity using specific monoclonal antibodies, suggesting the involvement of gelatinase-B as a mediator of HPC mobilization. These results are consistent with the hypothesis that neutrophils are major regulators of stem-cell mobilization through the release of metalloproteinases (MMPs) that cleave extracellular matrix molecules to which HPC are attached.
 ...
PMID:The role of metalloproteinases and adhesion molecules in interleukin-8-induced stem-cell mobilization. 1071 55

Alcohol intoxication impairs neutrophil function and increases host susceptibility to Streptococcus pneumoniae. In a rat model of pneumonia, the effects of acute intoxication were monitored for lung chemokine responses, neutrophil recruitment, and bactericidal activity. Alcohol delayed lung neutrophil recruitment, increased bacterial burden, and decreased survival. Before neutrophil recruitment, bronchoalveolar lavage (BAL) macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) were decreased by alcohol. This alcohol-induced effect was reversed at 6 h, when there were large numbers of neutrophils in control BAL fluid, compared with the alcohol-treated group. Cyclophosphamide-induced neutropenia decreased neutrophil recruitment, minimizing the effects of recruited neutrophils on chemokine levels, and extended the alcohol-induced chemokine suppression. MIP-2 and CINC mRNA contents also were suppressed by alcohol 4 and 6 h after infection. Thus, alcohol suppresses lung chemokine activity in response to S. pneumoniae, which is associated with delayed neutrophil delivery, elevated bacterial burden, and increased mortality.
 ...
PMID:Acute ethanol intoxication suppresses lung chemokine production following infection with Streptococcus pneumoniae. 1159 36

The expression and the functional activities of different chemokine receptors (CC motif: CCR1, CCR2, CCR3, CCR5, CCR6; CXC motif: CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) were investigated in 12 patients with lymphoproliferative disease of granular lymphocytes (LDGL). Six patients were characterized by the proliferation of CD3+ve GL and six patients by the expansion of CD3-ve GL. The interleukin 8 (IL-8/CXCL8) receptor CXCR1 was expressed in 12/12 patients, the CXCR4 in 6/12 patients (four CD3+ve and two CD3-ve) and the CXCR3 in 3/12 patients (one CD3+ve and two CD3-ve). CXCR1 was expressed only by proliferating GL. Other CC and CXC receptors were not expressed on proliferating GL (< 2%). In functional assays, purified GL from the patients displayed significant migration in response to specific chemokines, indicating that CXCR1, CXCR3 and CXCR4 were functionally active in these patients. In addition, a significant reduction of IL-8/CXCL8-mediated cell migration was reported in the presence of anti-CXCR1 monoclonal antibody. Our results indicate that expanding cells from patients with LDGL express specific CXCR. These data may help to define functional properties of proliferating GL in patients with LDGL and contribute toward the understanding of the complex clinical features of this disease. In particular, as CXCR1 was expressed in all of the patients studied, we speculate that abnormal expression of this receptor on proliferating GL might play a role in the pathogenesis of neutropenia, which represents a common feature in LDGL patients.
 ...
PMID:Upregulation of CXCR1 by proliferating cells in patients with lymphoproliferative disease of granular lymphocytes. 1261 7

The identification of chemokines has profoundly changed the way we interpret the immune response, elucidating the mechanism by which inflammatory cells are recruited to the site of infection by local secretion of chemoattractants such as CXC chemokine ligand 8 (CXCL8)/interleukin-8, chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1. This novel view of the immune response has been remodeled further following observations that lymphoid tissue development derives from the coordinated secretion of homeostatic chemokines such as CCL19, CCL21, and CXCL13, which mediate recruitment and clustering of the cells involved in lymphoid organogenesis. The study of primary immunodeficiencies has demonstrated that the number of circulating leukocytes is dependent on migration amongst bone marrow, blood circulation, and inflamed tissues. Defects of leukocyte adhesion and chemotaxis as a result of mutations of beta2-integrins lead to abnormal leukocytosis and susceptibility to skin infections, as observed in leukocyte adhesion deficiency. Conversely, neutropenia in children with myelokathexis is a result of leukocyte retention in the bone marrow because of the mutations of CXC chemokine receptor 4, which affect the capacity of cells to recirculate between blood and bone marrow. Moreover, the identification of the genetic basis of primary immunodeficiencies has shown that many primary immunodeficiencies such as Wiskott-Aldrich syndrome and common variable immunodeficiencies are characterized by altered migration of leukocytes and/or disregulation of cellular response to chemokines. This paper will be focused on the interpretation of primary immunodeficiencies as defects in leukocyte circulation between blood and primary and secondary organs.
 ...
PMID:Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients. 1507 52

Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disease often associated with autoimmune disorders such as rheumatoid arthritis. High levels of soluble Fas ligand have been implicated in development of chronic neutropenia. However, a comprehensive analysis of constitutive chemokine and lymphokine production in LGL leukemia has not previously been reported. Here, we utilized RNase protection assays and enzyme-linked immunosorbent assays (ELISAs) to address this question. RANTES, IL-8, MIP-1alpha, MIP-1beta, IL-1beta, IL-10, IL-12 p35, IL-18, IFN-gamma and IL-1Ra were the cytokine transcripts expressed in elevated levels from RNA of peripheral blood mononuclear cells of LGL leukemia patients. Confirmatory ELISAs indicated that sera from LGL leukemia patients have elevated levels of RANTES, MIP-1beta, IL-18, and to a lesser extent IL-8 and IL-1Ra. This pattern of cytokine upregulation is similar to that seen in some chronic infections or in autoimmune diseases, thus characterizing LGL leukemia as a proinflammatory disorder.
 ...
PMID:Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. 1564 40


1 2 3 4 Next >>