Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in a murine model of pneumococcal pneumonia was examined. Intranasal inoculations were 10(7) cfu/mouse (high inoculum) and 5 x 10(4) cfu/mouse (low inoculum) of Streptococcus pneumoniae, which induced severe or mild lung inflammation, respectively. With the low inoculum, rhG-CSF significantly improved survival when initiated 24 h or 10 min before, but not when initiated 24 h after, infection. Pretreatment with rhG-CSF significantly increased myeloperoxidase (MPO) activity in lungs 8 h after the infection and increased circulating neutrophil count 24, 48, and 72 h after infection. In contrast, rhG-CSF did not improve survival of animals infected with the high inoculum and did not increase MPO activity or neutrophil count in blood over those of sham-treated controls. These data strongly suggest that the severe inflammatory response typically observed in pneumococcal pneumonia recruits a maximum number of neutrophils in the lungs and thus masks the beneficial effect of rhG-CSF.
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PMID:Efficacy of recombinant human granulocyte colony-stimulating factor in a murine model of pneumococcal pneumonia: effects of lung inflammation and timing of treatment. 1108 2

We investigated the roles of neutrophil and neutrophil elastase in acute lung injury (ALI) to elucidate the mechanism of ALI. We designed two protocols. Protocol I: Experimental ALI was induced by endotoxin (0.02 mg/kg) and platelet-activating factor (8 microg/kg/4 h) in untreated rabbits (control group I), in neutropenic rabbits pretreated with nitrogen-N-oxide hydrochloride, and in untreated rabbits infused with a neutrophil elastase inhibitor (ONO-5046; 20 mg/kg/4 h). Protocol II: ALI was induced by smaller doses of endotoxin (0.015 mg/kg) and platelet-activating factor (7 microg/kg/4 h) than those used in protocol I in untreated rabbits (control group II), in neutrophilic rabbits pretreated with human recombinant granulocyte colony-stimulating factor, and in neutrophilic rabbits infused with ONO-5046 (as in protocol I). The severity of ALI was assessed by the protein concentration, the elastase activity in the bronchoalveolar lavage fluid, and the histologic pulmonary edema ratio. The degree of pulmonary neutrophil accumulation was assessed by pulmonary myeloperoxidase activity and histological findings. Both ALI and pulmonary neutrophil accumulation were suppressed by neutropenia (protocol I), while they were exacerbated by neutrophilia (protocol II). The neutrophil elastase inhibitor could suppress ALI, but it could not suppress pulmonary neutrophil accumulation in both untreated and neutrophilic rabbits (protocols I and II). These findings indicate that neutrophils play an important role in the pathogenesis of ALI via neutrophil elastase.
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PMID:Neutrophils mediate acute lung injury in rabbits: role of neutrophil elastase. 1118 17

We experienced the case of an 82-year-old man with chronic neutrophilic leukemia (CNL) with dysplastic features in the granulocytic lineage which subsequently progressed to acute myeloblastic leukemia (AML) with myelofibrosis. The patient had hepatosplenomegaly, but there was no evident cause of neutrophilic leukocytosis. The cytogenetic study showed that he had a normal karyotype. Concentrations of the serum granulocyte colony-stimulating factor (G-CSF) were not detectable. Two years after the diagnosis of CNL, blastic transformation to AML occurred with myelofibrosis and significant morphological abnormalities in neutrophils. The blasts were positive for myeloperoxidase, CD33, CD34, and HLA-DR, and the presence of dysplasia within the granulocytic lineage suggested that he had an abnormality at the level of the granulocyte-committed progenitors. Heterogeneous origins of CNL might lead to various clinicopathological features in each case.
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PMID:Evolution to acute myeloblastic leukemia from chronic neutrophilic leukemia with dysplastic features in granulocytic lineage. 1127 13

Histone acetylation has been shown to affect chromatin structure and gene expression. The mitogen-activated protein (MAP) kinase pathway is activated by a number of cytokines and plays critical roles in hematopoietic cell survival, proliferation, and differentiation. We focused on the part of the MAP kinase cascade and granulocyte colony-stimulating factor (G-CSF)in histone acetylation at one of the critical myeloid differentiation-associated genes, myeloperoxidase (MPO). G-CSF caused rapid acetylation of histone H3 and H4 at the promoter of MPO as revealed by chromatin immunoprecipitation. In addition, CBP and p300 were recruited to the promoter in response to G-CSF. Furthermore, we showed that rapid histone acetylation induced by G-CSF is MAP kinase-dependent. These results illustrate how myeloid-differentiating signals via G-CSF may be coupled with histone acetylation during the process of gene expression.
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PMID:Histone acetylation induced by granulocyte colony-stimulating factor in a map kinase-dependent manner. 1134 75

After abdominal trauma, the lung is susceptible to secondary injury caused by acute neutrophil (PMN) sequestration and alveolar capillary membrane disruption. Adenosine is an endogenous anti-inflammatory metabolite that decreases PMN activation. AICAR ([5-amino-1-[beta-D-ribofuranosyl]imidazole-4-carboxamide]riboside) is the prototype of a novel class of anti-inflammatory drugs that increase endogenous adenosine. After trauma, AICAR administration has been shown to decrease secondary lung injury in models of hemorrhagic shock with delayed lipopolysaccharide challenge and pulmonary contusion. However, early suppression of PMN activation could worsen outcomes after penetrating abdominal trauma. We hypothesized that, after penetrating abdominal trauma, the ideal resuscitation strategy would involve early, short-lived suppression of PMN activation to minimize secondary lung injury, followed by later enhancement of PMN chemotaxis and phagocytosis [using granulocyte colony-stimulating factor (G-CSF)] to lessen late septic complications. G-CSF has not been shown to potentiate PMN mediated pulmonary reperfusion injury. Swine were subjected to cecal ligation/incision and hemorrhagic shock (trauma), followed by resuscitation with shed blood, crystalloid, and either G-CSF, a combination of G-CSF and AICAR, or 0.9% normal saline. At 72 h, bronchoalveolar lavage (BAL) leukocyte counts and protein concentration were determined, and lung tissue analysed for myeloperoxidase (MPO, a measure of PMN infiltration) and microscopic pathology. Analysis of BALs revealed a significant increase protein concentrations and in white blood cell and PMN infiltration (P< 0.05) following trauma. These acute changes were not exacerbated by G-CSF, but were reversed by combined AICAR + G-CSF, which implicates a physiologic role for adenosine. This suggests that combination therapy may have beneficial effects on the lung after trauma.
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PMID:Combination therapy that targets secondary pulmonary changes after abdominal trauma. 1138 22

Autoimmune neutropenia (AIN) has been reported in infants and children, but not in neonates. AIN is caused by antibodies produced by the patient against their own neutrophils; therefore, it differs from the more common alloimmune neonatal neutropenia and the neonatal neutropenia because of a maternal autoimmune disease in which antineutrophil antibodies of maternal origin cross the placenta. We observed 2 cases of congenital AIN in premature neonates. These are the youngest reported cases, and indicate that AIN can have a prenatal onset. Examination of the bone marrow biopsies revealed an increase in B lymphocytes and myeloperoxidase-positive cells with a maturation arrest at the myelocyte stage. Recombinant human granulocyte colony-stimulating factor effectively treated the neutropenia, as it does in infantile AIN. Ten months after the diagnosis, 1 of the patients still requires recombinant human granulocyte colony-stimulating administration.
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PMID:Congenital autoimmune neutropenia in two premature neonates. 1143 74

Stimulation with granulocyte colony-stimulating factor (G-CSF) induces myeloid precursor cells to differentiate into neutrophils, and tyrosine phosphorylation of certain cellular proteins is crucial to this process. However, the signaling pathways for neutrophil differentiation are still obscure. As the Src-like tyrosine kinase, Lyn, has been reported to play a role in G-CSF-induced proliferation in avian lymphoid cells, we examined its involvement in G-CSF-induced signal transduction in mammalian cells. Expression plasmids for wild-type Lyn (Lyn) and kinase-negative Lyn (LynKN) were introduced into a murine granulocyte precursor cell line, GM-I62M, that can respond to G-CSF with neutrophil differentiation, and cell lines that overexpressed these molecules (GM-Lyn, GM-LynKN) were established. Upon G-CSF stimulation, both the GM-Lyn and GM-LynKN cells began to differentiate into neutrophils, showing early morphological changes within a few days, much more rapidly than did the parental cells, which started to exhibit nuclear lobulation about 10 days after the cells were transferred to G-CSF-containing medium. However, the time course of expression of the myeloperoxidase gene, another neutrophil differentiation marker, was not affected by the overexpression of Lyn or LynKN. Therefore, in normal cells, protein interactions with Lyn, but not its kinase activity, are important for the induction of G-CSF-induced neutrophilic nuclear lobulation in mammalian granulopoiesis.
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PMID:Acceleration of granulocyte colony-stimulating factor-induced neutrophilic nuclear lobulation by overexpression of Lyn tyrosine kinase. 1178 33

Internal tandem duplication (ITD) mutations of the juxtamembrane domain-coding sequence of the FLT3 gene are found in up to 34% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITDs result in constitutive activation of the tyrosine kinase domain and transform growth factor-dependent cell lines. FLT3 activation leads to antiapoptotic and proliferative signals, but little is known about the impact of FLT3/ITDs on differentiation. This study was designed to investigate the effect of FLT3/ITD expression on the differentiation of the 32Dcl3 (32D) myeloblastic cell line to neutrophils in response to granulocyte colony-stimulating factor (G-CSF). Expression of FLT3/ITD completely blocked morphologic differentiation and induction of myeloperoxidase (MPO), lysozyme, and CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) in response to G-CSF. Wild-type FLT3 and vector-transfected 32D cells were able to differentiate, although the maturation of FLT3-transfected cells was delayed by FLT3 ligand (FL) stimulation. CEP-701, a potent FLT3 tyrosine kinase inhibitor, overcame the morphologic block in differentiation caused by FLT3/ITD expression and allowed G-CSF induction of myeloid maturation markers. These findings suggest that blocking differentiation may be one of the mechanisms by which FLT3/ITDs contribute to leukemogenesis. CEP-701 and other FLT3 inhibitors may be useful for overcoming the block to differentiation (as well as the block to apoptosis) in the leukemic cells of patients with AML.
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PMID:Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. 1239 74

The aims of this study were to examine the plasma concentrations of inflammatory mediators including cytokines induced by a single bout of eccentric exercise and again 4 weeks later by a second bout of eccentric exercise of the same muscle group. Ten untrained male subjects performed two bouts of the eccentric exercise involving the elbow flexors (6 sets of 5 repetitions) separated by four weeks. Changes in muscle soreness, swelling, and function following exercise were compared between the bouts. Blood was sampled before, immediately after, 1 h, 3 h, 6 h, 24 h (1 d), 48 h (2 d), 72 h (3 d), 96 h (4 d) following exercise bout to measure plasma creatine kinase (CK) activity, plasma concentrations of myoglobin (Mb), interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), myeloperoxidase (MPO), prostaglandin E2 (PGE2), heat shock protein (HSP) 60 and 70. After the first bout, muscle soreness increased significantly, and there was also significant increase in upper arm circumference; muscle function decreased and plasma CK activity and Mb concentration increased significantly. These changes were significantly smaller after the second bout compared to the first bout, indicating muscle adaptation to the repeated bouts of the eccentric exercise. Despite the evidence of greater muscle damage after the first bout, the changes in cytokines and other inflammatory mediators were quite minor, and considerably smaller than that following endurance exercise. These results suggest that eccentric exercise-induced muscle damage is not associated with the significant release of cytokines into the systemic circulation. After the first bout, plasma G-CSF concentration showed a small but significant increase, whereas TNF-alpha and IL-8 showed significant decreases compared to the pre-exercise values. After the second bout, there was a significant increase in IL-10, and a significant decrease in IL-8. In conclusion, although there was evidence of severe muscle damage after the eccentric exercise, this muscle damage was not accompanied by any large changes in plasma cytokine concentrations. The minor changes in systemic cytokine concentration found in this study might reflect more rapid clearance from the circulation, or a lack of any significant metabolic or oxidative demands during this particular mode of exercise. In relation to the adaptation to the muscle damage, the anti-inflammatory cytokine IL-10 might work as one of the underlying mechanisms of action.
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PMID:Changes in inflammatory mediators following eccentric exercise of the elbow flexors. 1563 88

There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multiple sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells. In CSF supernatants relative to controls, IL-17, MIP-1beta, IL-1beta and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-alpha was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS-multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-gamma+IL-4- T-cell percentage and intracellular IFN-gamma/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patients showed not only a significantly greater percentage of IFN-gamma+IL-4- T cells than controls but also a significantly higher percentage of IFN-gamma-IL-4+ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and IL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.
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PMID:Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. 1574 72


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