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

Pharmacological strategies which limit neutrophil recruitment may also limit the damage induced by the reperfusion of an ischemic vascular territory. In the present study, we have investigated the effects of the BLT receptor antagonist, CP-105,696 ((+)-1-(3S,4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl]-cyclopentane carboxylic acid), on the local, remote and systemic inflammatory changes observed during severe intestinal ischemia (120 min) and reperfusion (120 min) injury. The post-ischemic treatment with CP-105,696 (3 mg/kg) virtually abolished the increase in vascular permeability, but not neutrophil accumulation, in the intestine and lungs. CP-105,696 partially inhibited the reperfusion-induced neutropenia, but failed to affect intestinal haemorrhage or lethality. CP-105,696 had no inhibitory effect on the local and systemic increases in the concentrations of tumour necrosis factor (TNF-alpha), interleukin-1 beta and interleukin-10, but markedly suppressed interleukin-6. Overall, our results show that activation of BLT receptor plays a minor role in the local, remote and systemic injuries following severe ischemia and reperfusion in rats.
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PMID:Effect of a BLT receptor antagonist in a model of severe ischemia and reperfusion injury in the rat. 1195 89

1. Pirfenidone, an antifibrotic compound with anti-inflammatory effects, has been investigated in a rat model of acute experimental ischaemia-reperfusion injury of the small intestine. 2. Occlusion of the superior mesenteric artery in young adult female rats for 30 min followed by reperfusion for 120 min induced significant local and systemic effects, including tissue haemorrhage with oedema, elevated serum concentrations of tumour necrosis factor (TNF)-alpha, neutropenia, hypotension and bradycardia. 3. Administration of pirfenidone (200 mg/kg, p.o., i.v. or i.p.) 30 min before occlusion completely inhibited the increase in serum TNF-alpha concentrations. Pirfenidone inhibited, but did not completely prevent, tissue damage in the small intestine, as well as hypotension and oedema, but neutropenia and bradycardia were not significantly changed by treatment. 4. Thus, pirfenidone effectively moderates both local and some systemic effects of ischaemia-reperfusion injury in the rat small intestine model.
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PMID:Pirfenidone attenuates ischaemia-reperfusion injury in the rat small intestine. 1236 91

We previously found that the peripheral blood (PB) mononuclear cells (MCs) (PBMCs) of a patient with chronic neutropenia contained an expanded population of cytotoxic CD8+ T cells using a variable (V) region delta1 gene product in the T-cell receptor-alpha (TCR-alpha) polypeptide [Vdelta1-constant(C)alpha+ T cells]. Sequencing of polymerase chain reaction (PCR) amplification products have now revealed a productive Vdelta1/joining (J)alphaIGRJa03/Calpha rearrangement of the TCR-alpha gene, predominantly associated with a Vbeta16/Dbeta2.1/Jbeta2.1/Cbeta2 TCR-beta gene, in these cells. Furthermore, we detected a markedly deficient proliferative response of the patient PBMCs to triggering with monoclonal antibodies (MoAbs) to the CD3 molecule, contrasting with a substantial response to the Vbeta3, 12, 14, 15, 17 and 20-specific staphylococcal enterotoxin B (SEB) superantigen, suggesting defective TCR-mediated activation of the Vdelta1+/Vbeta16+ clone. Moreover, whereas triggering of Vdelta1- T cells cultured with interleukin-2 (IL-2) by MoAb to the CD3 molecule enhanced proliferation, Vdelta1-Calpha+ T cells were inhibited by MoAbs to either CD3 or Vdelta1. Vdelta1-Calpha+ T-cell clones spontaneously secrete interferon-gamma (IFN-gamma) and were further induced to release tumour necrosis factor (TNF-alpha) when triggered by anti-CD3 plus phorbol ester. Aberrant signalling by the clonotypic TCR together with the functional properties of the CD8+ Vdelta1+/Vbeta16+ clone may thus contribute to the immunohaematological abnormalities observed in this patient.
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PMID:Aberrant T-cell receptor signalling of interferon-gamma- and tumour necrosis factor-alpha-producing cytotoxic CD8+ Vdelta1/Vbeta16 T cells in a patient with chronic neutropenia. 1282 63

The cytokine granulocyte colony-stimulating factor (G-CSF) is in broad clinical use to treat neutropenia, and trials on its use in immunosuppressed conditions and infections are ongoing. To apply G-CSF effectively, it is crucial to understand the regulation and distribution of its endogenous formation. Since G-CSF release is mediated, at least in part, by TNF-alpha formation, we investigated whether drugs suppressing TNF-alpha also impair G-CSF production. Surprisingly, G-CSF formation was enhanced in lipopolysaccharide (LPS)-stimulated blood from a pentoxifylline-treated patient. In the presence of dibutyryl-cAMP, forskolin, tolafentrine or 3-isobutyl-1-methylxanthine, LPS-induced G-CSF formation was enhanced in THP-1 cells, primary monocytes and whole blood. Correspondingly,rp-8-bromo-cAMP suppressed LPS-induced G-CSF release. Addition of prostaglandin E(2) enhanced and indomethacin suppressed G-CSF formation. Reporter gene studies showed that dibutyryl-cAMP enhanced LPS-induced G-CSF promoter activity, indicating a transcriptional up-regulation. Furthermore, disruption of a newly identified putative cAMP-responsive element (CRE) in the G-CSF promoter demonstrated the regulatory role for G-CSF gene transcription. In conclusion, endogenous G-CSF formation critically depends on both TNF-alpha and cyclooxygenase products, exerting effects via cAMP and the CRE in the G-CSF promoter. This might have bearing for drug side effects, putative G-CSF mimetics and our understanding of G-CSF immunobiology.
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PMID:Cyclic AMP increases endogenous granulocyte colony-stimulating factor formation in monocytes and THP-1 macrophages despite attenuated TNF-alpha formation. 1288 4

Neutropenia has been shown to markedly increase plasma TNF-alpha concentration after LPS injection and to enhance LPS-induced mortality. Experiments reported here demonstrate that the 15-fold higher plasma TNF-alpha concentration elicited by LPS in neutropenic vs. nonneutropenic unanesthetized mice correlated with increased hepatic and splenic, but not pulmonary, TNF-alpha mRNA. Core 2 beta-1,6-N-acetylglucosaminyltransferase-null and CD18-deficient mice also exhibited exaggerated plasma TNF-alpha responses to LPS injection. Findings suggest that extravasated neutrophils inhibit systemic TNF-alpha production and that they do so through organ-selective mechanisms involving CD18 integrin and selectin binding.
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PMID:Transcriptional regulation of TNF-alpha production in neutropenia. 1545 67

The aim of our study was to investigate the roles played by sphingosine kinase (SPHK) in the anaphylatoxin C5a-triggered responses in vivo. Our data show that i.v. administration of C5a triggers a rapid neutropenic response, but pretreating mice with the SPHK inhibitor, N,N-dimethylsphingosine (DMS), 10 min before the C5a i.v. administration substantially inhibited the C5a-triggered neutropenia. Similarly the i.v. administration of C5a caused a rapid increase in the serum levels of TNF-alpha and IL-6, and this increase in cytokine levels was blocked by DMS. We then induced acute peritonitis with C5a. The C5a i.p. injection triggered a fast recruitment of neutrophils, later followed by monocytes, into the peritoneal cavity. Vascular permeability was also observed: when we i.v. injected Evans blue before C5a i.p. injection, we could observe a continued influx of the dye into the peritoneum. In mice pretreated with DMS, there was a significant reduction on the C5a-triggered neutrophil and monocyte infiltration, as well as a marked reduction on the Evans blue influx. Our data also show that the i.p. administration of C5a caused a rapid increase in TNF-alpha and IL-6 levels in the peritoneal cavity, and this increase in cytokine levels was substantially inhibited in mice pretreated with the SPHK inhibitor. Taken together, these observations suggest a potential role for SPHK in the C5a-triggered inflammatory responses in vivo.
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PMID:A critical role for sphingosine kinase in anaphylatoxin-induced neutropenia, peritonitis, and cytokine production in vivo. 1587 48

Neutropenia may necessitate polymorphonuclear (PMN) transfusion, but among other reasons, PMN short shelf-life complicates realization of innovative transfusion strategies. In 18 donors, PMNs were mobilized using rHuG-CSF + dexamethasone. (8.3 +/- 1.6) x 10(10) PMNs were harvested in 203 +/- 8.7 mL. PMNs were stored undiluted (1, n = 18) and diluted 1-in-2, 1-in-4, 1-in-8 using T-Sol (2, n = 6), T-Sol + 1% HSA (3, n = 6), or autologous plasma (4, n = 6) for 72 h. Haemograms, pH values, phagocytosis, oxidative burst, and interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha levels were assessed every 24 h. PMN count decreased from (4.3 +/- 0.8) x 10(10) to (2.2 +/- 1.0) x 10(10), and pH value dropped from 6.4 +/- 0.3 to 5.4 +/- 0.2 within 72 h (1), whereas 1-in-4 and 1-in-8 dilutions exhibited consistent haemograms and pH values above 6.0. 1-in-8 dilution (4) stabilized pH at 7.1 +/- 0.4 after 72 h. Function deteriorated to about 50% within 24 h (1), but 1-in-8 (3), 1-in-4 and 1-in-8 diluted PMNs (4) kept it >90% for 72 h. In all collectives, cytokine levels increased during storage. After all, IL-1beta ranged between 31.0 +/- 16.3 (1-in-4, 4) and 100.0 +/- 21.4 (1-in-4, 2), IL-8 from 513 +/- 454 (1) to 3180 +/- 760 (1-in-8, 2), and TNF-alpha between 3.8 +/- 1.7 (1-in-2, 2) and 23.2 +/- 11.8 (1-in-8, 4) (pg mL(-1)). PMN function may be preserved for 72 h in vitro by dilution of PMN apheresates with, preferably, autologous plasma.
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PMID:Storage of neutrophil granulocytes (PMNs) in additive solution or in autologous plasma for 72 h. 1594 7

Clinical and laboratory data indicate that the liver plays an important role in the incidence, pathogenesis, and outcome of acute lung injury/acute respiratory distress syndrome. To distinguish direct effects of endotoxin on the lungs from liver-dependent effects during the early phase of the response to endotoxemia, we used an in situ perfused piglet preparation in which only the ventilated lung or both the lung and liver could be included in a blood perfused circuit. We monitored pulmonary vascular resistance, oxygenation, neutrophil count, lung edema as reflected by wet-dry weights of lung tissue, perfusate concentrations of TNF-alpha, IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF-kappaB) in lung tissue before and for 2 h after endotoxin. When only the lung was perfused, endotoxin caused pulmonary hypertension and neutropenia; but oxygenation was maintained; TNF-alpha, IL-6, and 8-isoprostane levels were minimally elevated; and there was no lung edema. When both the liver and lung were perfused, endotoxin caused marked hypoxemia, large increases in perfusate TNF-alpha, IL-6, and 8-isoprostane concentrations, and severe lung edema. NF-kappaB activation in the lung was greatest when the liver was in the perfusion circuit. We conclude that the direct effects of endotoxemia on the lungs include vasoconstriction and leukocyte sequestration, but not lung injury. Intense activation of the inflammatory response and oxidative injury that results in pulmonary edema and hypoxemia (acute lung injury) requires interaction of the lungs with the liver.
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PMID:Endotoxin-induced acute lung injury requires interaction with the liver. 1600 84

The objective of this study is to determine if heat stress prior to endotoxemia diminishes cardiopulmonary dysfunction by attenuating the cytokine inflammatory response. Rats were assigned to either: 1) neutropenia; 2) heat; 3) neutropenia, LPS; or 4) heat, neutropenia, LPS. Heart rate, blood gases, and blood, lung lavage, and lung mRNA for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and macrophage inflammatory protein (MIP)-2 were measured. Heat given before LPS resulted in a similar A-a O(2) gradient as the heat-alone and neutropenic groups (8 +/- 8 versus 8 +/- 7 versus 4 +/- 3 mm Hg) and a lower A-a O(2) gradient when compared to the neutropenic, LPS rats (8 +/- 8 versus 22 +/- 8 mm Hg, p < 0.003). Blood, lung lavage, and lung mRNA for TNF-alpha, IL-1beta, and MIP-2 were similar in the LPS rats regardless of heat. Heart rate was similar in both LPS groups but higher than non-LPS groups. Heat pretreatment attenuates lung injury in the neutropenic, endotoxemic rat but not by decreasing TNF-alpha, IL-1beta, or MIP-2 in the lung. Heat prior to LPS did not prevent cardiac dysfunction in neutropenic rats.
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PMID:Heat stress protects against lung injury in the neutropenic, endotoxemic rat. 1650 46

Variability in the efficacies and toxicities of anticancer agents is a major problem. We hypothesized that polymorphisms in cytokine gene promoters may underlie genetic susceptibility to chemotherapy-induced toxicities in the Japanese. DNA was extracted from 100 patients undergoing 5-fluorouracil plus cisplatin chemotherapy. We used a case-only design to evaluate the relation between toxicities and cytokine promoter gene polymorphisms. The following polymorphisms were genotyped: tumor necrosis factor (TNF)-alpha-1031T/C, interleukin (IL)-1beta-511C/T, IL-6-634C/G, IL-10-819T/C, IL-18-137G/C, macrophage migration inhibitory factor -173G/C, and 86-basepair variable numbers of tandem repeat in intron 2 of the IL-1 receptor antagonist. The frequency of the IL-6-634 GC and GG genotypes was significantly higher in patients with grades 1-4 leukopenia (P=0.003; Crude-odds ratios (Cr-OR) =4.0), neutropenia (P=0.0051; Cr-OR=3.6), or thrombocytopenia (P<0.0001; Cr-OR=6.1) than in patients without these toxicities. Similarly, the frequency of the IL-1beta-511 TC and TT genotypes and the frequency of the TNF-alpha-1031 TT genotype were significantly higher in patients with grades 1-4 thrombocytopenia (P=0.015; Cr-OR=2.9) and stomatitis (P=0.02; Cr-OR=3.1), respectively. Multivariate analysis of factors such as age, sex, disease type, purpose of the chemotherapy, use of radiotherapy, and cytokine promoter gene polymorphisms showed polymorphisms to be significant predictors of toxicity. Our results suggest that polymorphisms in cytokine gene promoters may be associated with susceptibilities to leukopenia, neutropenia, thrombocytopenia and stomatitis in patients treated with 5-fluorouracil plus cisplatin.
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PMID:Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy. 1682 Sep 19


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