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)

The leukocytosis activity of C5a was studied in a rabbit model. Blood samples were drawn for cell counts through a catheter placed in an artery of one rabbit ear after injection of either porcine or human C5a into a vein in the opposite ear. These studies indicate the potential of C5a to mobilize bone marrow neutrophils following transient C5a-induced neutropenia, based on counts of nonsegmented neutrophils. The numbers of circulating neutrophils can be selectively elevated by 300% to 400%, within 1 to 2 hours, in rabbits given only microgram quantities (1 to 5 x 10(-9) mol/l) of C5a or C5adesArg. These quantities of C5a are equivalent to 1% to 2% of complement C5 activation. The time-course of the induced neutrophilia is characteristic of C5a, increasing rapidly in the first 10 to 20 minutes after injection and attaining a maximum level at 2 to 5 hours, then decreasing slowly to normal levels over the next 4 to 6 hours. After boiling at 100 degrees C for 10 minutes, C5a (C5ades Arg) lost its leukocytosis activity, indicating that the cellular effect was not caused by endotoxin. Other known leukocytosis factors, such as epinephrine, dexamethasone, lipopolysaccharide, and the prostanoid 15(S)-15-methyl PGF2 alpha, produced a distinctly different profile of leukocyte mobilization than that of C5a. The C5a-induced neutrophilia was not inhibited by pretreating these animals with indomethacin, suggesting that it is not a prostanoid-induced effect. One hypothesis is that no secondary cellular mediator system is involved in C5a-mediated leukocytosis, but rather than C5a alone is responsible for a rapid mobilization of neutrophils from bone marrow pools, and perhaps marginated pools, following neutropenia. Circulating neutrophils are activated by C5a and thereby become deformed and adherent, leading to a neutropenia, sequestration, and depletion of cells. After the neutropenic event an immediate neutrophilic response is required for replacement of this particular cell population and to re-establish homeostasis. Therefore the role of C5a may be just as important as other known leukocytosis factors (fragments from C3, for example) in promoting complement-dependent neutrophil mobilization in response to tissue injury, infections, or extracorporeal blood treatments.
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PMID:C5a-induced neutrophilia. A primary humoral mechanism for recruitment of neutrophils. 238 4

1. The characteristics of N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced oedema formation were investigated in vivo in rabbit skin. 2. FMLP injected intradermally alone induced a small increase in plasma leakage, but marked synergism with prostaglandin E2 (PGE2) in producing oedema responses was observed. In the presence of PGE2, FMLP was equiactive with C5a des Arg and 100-1000 times more active than histamine in terms of permeability-increasing activity. The response to FMLP was not dependent on endogenous histamine release. 3. FMLP-induced responses were of long duration (t1/2 approximately 40-50 min) when compared with bradykinin (t1/2 approximately 4-5 min). 4. The activity of a range of N-formyl peptides in increasing vascular permeability in skin correlated well with their activity as neutrophil stimulants in vitro. 5. Intravenous infusion of zymosan-activated plasma (ZAP) resulted in transient neutropenia and inhibition of oedema formation induced by FMLP and C5a des Arg in the skin. Responses to bradykinin were unaffected by the infusion of ZAP. 6. Intravenous injection of the non-steroidal antiinflammatory drug, ibuprofen, resulted in an inhibition of FMLP-induced, but not histamine-induced, oedema formation. This effect was independent of cyclo-oxygenase inhibition and the drug did not induced neutropenia. 7. Intravenous injection of the microtubule blocking agent colchicine inhibited FMLP-induced oedema formation. Responses to bradykinin were unaffected. When colchicine was administered after intradermal FMLP, subsequent plasma leakage was abolished. 8. The inference that receptors have evolved to bacterial secretions (i.e. FMLP) and products of the interaction of bacterial cell walls with tissue fluid (i.e. C5a des Arg), is consistent with the hypothesis that oedema formation is fundamentally a functional process concerned with regulating microbial lysis and opsonisation in an infected tissue.
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PMID:Characteristics of oedema formation induced by N-formyl-methionyl-leucyl-phenylalanine in rabbit skin. 249 23

C3a, when injected intravenously in guinea-pigs, caused a rapid drop of circulating neutrophils and platelets. The neutropenia was reversible and followed by a neutrophilia, which reached about 200% of baseline values. Upon challenge with octa- and hexapeptide, mimicking the C-terminal sequence of C3a, neutrophils and platelets reacted in the same manner. The hexapeptide-desArg (pentapeptide without the C-terminal arginine of hexapeptide) induced no neutropenia but a significant neutrophilia. Likewise, when injected in animals with a genetic deficiency or dysfunction of the C3a-receptor, the hexapeptide caused no drop of the neutrophils, but a neutrophilia, indicating that both neutrophil reactions are mediated by different mechanisms. With the octapeptide in vivo dose-response studies were performed. Despite maximal doses of octapeptide about 40% of the neutrophils remained in circulation, indicating that some but not all PMNs are susceptible to C3a. By pretreating the animals with an inhibitor of the serum carboxypeptidase N (SCPN-Inh) the C3a-induced neutropenia could be significantly augmented. But intravenous application of the inhibitor itself caused a 20-40% reduction of neutrophils during the first hour after injection, followed by a neutrophilia. In histological studies the timecourse of neutrophil sequestration in the lung was established, showing that the initial high neutrophil content of the lung lasted for at least 1 h and declined thereafter. Structural derangements could not be detected. These observations stress the importance of C3a besides C5a as an important mediator of inflammatory processes in species, where the C3a-receptor is present on inflammatory cells such as granulocytes.
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PMID:In vivo effects of C3a on neutrophils and its contribution to inflammatory lung processes in a guinea-pig model. 326 Jan 58

Complement-mediated neutrophil activation (CMNA) has been implicated as an important pathophysiologic mechanism contributing to acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). Using cardiopulmonary bypass (CPB) as a clinical model for complement-mediated microvascular injury, we studied the effects of methylprednisolone (MPSS) pretreatment on manifestations of CMNA in 28 pediatric patients undergoing CPB. Six patients not receiving MPSS served as controls. Results demonstrated that MPSS did not prevent complement activation as noted by 4.5- and 7.7-fold increases in plasma C3a des Arg levels during and immediately after CPB, respectively. However, detectable in vivo and in vitro manifestations of CMNA were altered. Neutropenia during CPB was attenuated to 65% of prebypass values compared with 47% in the control group. Neutrophil selective chemotactic desensitization toward C5a/C5a des Arg during the on bypass and postbypass periods was evident in the control group (0.41 and 0.76 cm specific migration, respectively) and prevented in the MPSS group (1.55 and 2.00 cm specific migration, respectively). We conclude that CMNA during CPB is ameliorated and/or prevented by MPSS pretreatment. These findings suggest that MPSS pretreatment may ameliorate complement-mediated microvascular (lung) injury in CPB and ARDS.
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PMID:The effects of methylprednisolone on complement-mediated neutrophil activation during cardiopulmonary bypass. 373 45

We have previously shown a marked difference in the inflammatory response to human C5a or C5a des arginine (Arg) instilled in rabbit lungs. These studies raised the question of where C5a and C5a des Arg are processes in vivo and what role neutrophils may play in the tissue distribution of these two mediators. After intravenous injection of purified, biologically active 125I-C5a or 125I-C5a des Arg, adult rabbits were serially bled and then killed at various time intervals. Although greater than 50% of the injected radioactivity was cleared from the circulation within 2 min for both mediators, C5a des Arg persisted in the circulation longer than C5a. C5a instillation caused an acute neutropenia, whereas C5a des Arg caused a less severe and more prolonged neutropenia, preceding a neutrophilic response observed with both mediators. Clearance of the mediators was primarily seen in the highly vascularized organs: the lung, spleen, liver, and kidney. A time-dependent accumulation was seen initially in the lung, followed by the spleen, liver, and kidney. Histologic examination showed a marked increase in the number of neutrophils within the lung and spleen. Depletion of circulating neutrophils by nitrogen mustard pretreatment of rabbits showed no change in the amount of labeled mediator bound in the lung, whereas splenic accumulation was dependent on the presence of neutrophils. These results indicate that C5a and C5a des Arg are rapidly removed from the circulation by specific accumulation in vascularized tissues. Clearance by the lung was not affected by neutrophil depletion, whereas clearance by the spleen was dependent on neutrophils. These experiments further suggest there are neutrophil-dependent and neutrophil-independent mechanisms involved in the removal of C5a and C5a des Arg from the circulation and that binding of C5 fragments in the pulmonary vasculature may precede and then induce neutrophil sequestration.
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PMID:In vivo clearance and tissue distribution of C5a and C5a des arginine complement fragments in rabbits. 717 88

Platelet-activating factor (PAF) is released in vitro during human and rabbit polymorphonuclear neutrophil (PMN) aggregation induced by C5a anaphylatoxin, neutrophil cationic proteins (CP) and their carboxypeptidase-B-derived fragments, C5a des Arg and CP des Arg, as well as phagocytosis of opsonized baker's yeast particles and immune complexes (IC). Purified PAF itself is able to cause in vitro PMN aggregation. By using selective inhibitors, we show that PMN aggregation, induced either by PAF or by other soluble stimuli such as C5a, CP and their des Arg products, follows a similar metabolic pathway, which is both adenosine-diphosphate-(ADP)- and arachidonic acid (AA)- independent. The in vivo injection of purified PAF into rabbits leads both to formation of intravascular PMN aggregates and to development of acute neutropenia, which has the same features as those observed after challenge with IC, C5a and CP. In this respect, electron-microscopic studies of intravascular PMN aggregates in the pulmonary capillary network and glomeruli show identical ultrastructural patterns. Moreover, the intravascular release of PAF is demonstrated after the intravenous injection of IC and temporally correlated with the development of neutropenia. We suggest that PAF is probably the final, common, effector substance of IC-, C5a-, C5a-des-Arg-, CP-, CP-des-Arg-mediated PMN aggregation.
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PMID:Mediators of immune-complex-induced aggregation of polymorphonuclear neutrophils. II. Platelet-activating factor as the effector substance of immune-induced aggregation. 745 Sep 1

Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man.
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PMID:Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia. 783 64

We examined potential mechanisms responsible for the parenchymal lung injury seen in an animal model of smoke inhalation with concurrent inflammation. Rats injected with sterile glycogen and exposed to smoke generated by the nonflaming pyrolysis of combined Douglas fir wood and polyvinylchloride showed a 74% increase in 125I-albumin lung permeability and a fivefold increase in lung myeloperoxidase (MPO) compared with control rats. There was also a significant increase in plasma indices of oxidative injury in these animals. Compared with control animals, plasma concentrations of thiobarbituric acid reactive substances (TBARS) were elevated by 62%, the concentrations of reduced sulfhydryl groups declined by 37%, and the levels of dinitrophenylhydrazine-reactive proteins (DNPH-RP) were doubled. In addition, the plasma concentrations of nitrate (NO3-) in rats exposed to glycogen plus smoke were increased three times that of control animals. Injection of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), immediately after smoke exposure or induction of neutropenia using either nitrogen mustard or antineutrophil antiserum, abolished the increase in concentrations of circulating NO3-, and prevented changes in plasma concentrations of TBARS, DNPH-RP, lung MPO activity, and tissue permeability index. These data suggest that neutrophil activation and the production of nitric oxide-derived oxidants contribute to the lung and plasma indices of oxidative injury in this smoke inhalation model.
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PMID:Role of neutrophils and nitric oxide in lung alveolar injury from smoke inhalation. 804 12

We have studied the role of neutrophils and the effects of the chemotactic factor FMLP, using normal, neutropenic (after cyclophosphamide treatment) and C5a desArg-treated unanesthetized rabbits. The intravenous administration of FMLP in normal animals induces transient and dose-dependent hypotension, neutropenia and thrombocytopenia, with a maximal response in 3 minutes. When a bolus of 5 x 10(-9) moles FMLP was administered, maximal arterial hypotension (40 +/- 1.1 v.s. 90 +/- 1.1 mmHg in the controls, P < 0.001) accompanied by a significant increase in central venous pressure (0.89 +/- 0.9 v.s. -2.2 +/- 0.7 mmHg in the controls, P < 0.01) and a decrease in systemic vascular resistance (90 +/- 15.6 v.s 187 +/- 16.4 mmHg/L/min, P < 0.005). Plasma pH and bicarbonate were significantly reduced, with a parallel increase in plasma lactate levels. A similar reduction of arterial blood pressure was also noted in neutropenic animals (31 +/- 3% of pretreatment levels respectively). C5a des Arg caused neutropenia similar to that seen after 5 x 10(-9) moles FMLP (120 +/- 60/mm3 and 170 +/- 25/mm3 respectively), but it did not induce hypotension. These data suggest that simple neutrophil activation is not the mechanism of the FMLP-induced hypotension and that this chemotactic factor may interact with other cell types to produce its effects.
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PMID:Hemodynamic and metabolic effects of intravenous formyl-methionyl-leucyl-phenylalanine (FMLP) in rabbits. 917 5

Renal replacement therapy relies predominantly on the use of cellulose-based membranes. Such membranes have a biocompatibility profile which is inferior to membranes manufactured from synthetic polymers. Synthetically modified cellulose (SMC) is a new, low-flux haemodialysis membrane in which hydroxyl groups have been replaced with benzyl groups. The biocompatibility profile characterized by changes in white cell and platelet counts and the activation of complement components (C3a, C5a and C5b-9) have been studied in vivo and compared with those of cellulose acetate, unmodified cellulose (Cuprophan ) and low-flux polysulphone (Fresenius Polysulfone) in the same group of patients. For SMC, the white cell count at 15 min declined to 65.6% of pretreatment level, compared with 63.8% for the cellulose acetate, 79.6% for low-flux polysulphone and 28.1% for Cuprophan, thereafter returning to pretreatment levels. Both modified cellulose membranes were superior to unmodified cellulose (P = 0.001); the differences between the modified cellulose membranes were not significant statistically. The changes induced by all three cellulose-based membranes exceeded those for low-flux polysulphone (P = 0.001). Associated with the neutropenia was a reduction in platelet count, but this was independent of membrane type. The mean time-averaged concentrations of C3a(des Arg) over 150 min were 1168 ng ml(-1) (SMC), 1030 ng ml(-1) (cellulose acetate), 1297 ng ml(-1) (Cuprophan) and 790 ng ml(-1) (low-flux polysulphone). Equivalent values for C5a(des Arg) were 6.12 (SMC), 2.98 (cellulose acetate), 11.03 (Cuprophan) and 1.33 ng ml(-1) (low-flux polysulphone). C5b-9 values were 385 (SMC), 386 (cellulose acetate), 177 (Cuprophan) and 185 ng ml(-1) (low-flux polysulphone). For each of the complement components the differences between the membranes were significant [P = 0.0009 (C3a(des Arg)), P = 0.0001 (c5a(des Arg) and C5b-9)]. The levels of C5b-9 generated during dialysis also showed a significant positive correlation compared to C5a for all membranes considered as a single group (Pearson's correlation coefficient = 0.870, P = 0.0001). It is concluded that the modification of the cellobiosic unit is a promising approach to improve the biocompatibility profile of cellulose-based membranes. The two different methods of modification lead to similar improvements in biocompatibility compared with unmodified cellulose, but as yet do not match that of low-flux polysulphone.
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PMID:Synthetically modified cellulose: an alternative to synthetic membranes for use in haemodialysis? 930 19


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