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Biomedical subjects

J B Sedgwick

Publications and source records attributed to J B Sedgwick.

At least 37 records · Page 2Linked to original sources
PubMed1994

Eosinophil eicosanoid relations in allergic inflammation of the airways.

Eosinophils are prominent features of allergic inflammation and can contribute to this process through release of inflammatory enzymes, granule-associated proteins, and leukotriene products. There is considerable interest in the fact that selected cytokines enhance eosinophil generation of leukotrienes. Therefore, future directions must include efforts to identify factors that regulate eosinophil synthesis of leukotrienes and therapeutic agents that might control these specific inflammatory responses.

Asthma↗
PubMed1993

Adhesion proteins on airway eosinophils in allergy and asthma.

Adhesion to, and interaction with, airway endothelium, interstitial matrix and epithelium during migration to the allergen-challenged airways of allergic rhinitis and asthma patients may account for the observed functional upregulation (priming) of airway eosinophils compared with corresponding blood eosinophils.

Allergens↗
PubMed1993

IL-5 is the predominant eosinophil-active cytokine in the antigen-induced pulmonary late-phase reaction.

The mechanism of airway eosinophilia during antigen-induced inflammation was investigated by measurement of eosinophil-active cytokines utilizing an eosinophil survival assay. In the first study, 4 patients with allergic rhinitis underwent segmental bronchoprovocation (SBP) with low, medium, and high doses of ragweed extract instilled into different bronchial subsegments; bronchoalveolar lavage (BAL) fluids were collected from each segment 12 min and 48 h after challenge. Eosinophil granule proteins and eosinophil survival activity were significantly elevated in the 48-h (late-phase) BAL fluids from these segments. Correlations were observed between the concentrations of eosinophil granule proteins and eosinophil survival activity (rs = 0.717 to 0.880, p < 0.001) in BAL fluids. Eosinophil survival activity was completely neutralized by anti-IL-5 monoclonal antibody in five of the seven 48-h samples tested representing three of the 4 patients. In the two remaining samples, eosinophil survival activity was only partially neutralized by either anti-IL-5 antibody or anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) but was completely neutralized by anti-IL-5 and anti-GM-CSF in combination. Subsequently, in the second study, 10 patients with allergic rhinitis were challenged by SBP with ragweed extract. Eosinophil survival activity was significantly elevated in the 48-h BAL fluids; this activity was partially neutralized by anti-IL-5 antibody about (48%) and completely neutralized by the combination of anti-IL-5 and anti-GM-CSF antibodies. These findings suggest that the eosinophil survival activity in the late inflammatory lesions following SBP with allergen is mainly associated with IL-5, with small contributions from GM-CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Corticosteroid resistance in eosinophilic gastritis--relation to in vitro eosinophil survival and interleukin 5.

Eosinophilic gastritis is usually responsive to corticosteroid therapy. In some cases, large doses and protracted treatment are required. This report describes a case of eosinophilic gastritis that was partially corticosteroid resistant. To determine mechanisms that explain this patient's incomplete response to corticosteroid therapy, peripheral blood eosinophils and serum were isolated from the patient. We found the in vitro survival of the patient's eosinophils was prolonged. In addition, his serum both promoted in vitro eosinophil survival and nullified the survival inhibiting of effect of hydrocortisone (10 microM). Furthermore, antibody against interleukin 5 (IL5) partially inhibited the enhanced eosinophil survival produced by the patient's serum and completely blocked the decrease in survival resulting from hydrocortisone. These observations indicate that elevated circulating levels of IL5 may contribute to the peripheral eosinophilia and corticosteroid resistance in some patients with eosinophilic gastritis.

Adrenal Cortex Hormones↗
PubMed1992

Comparison of airway and blood eosinophil function after in vivo antigen challenge.

Eosinophils (EOS) are important effector cells in allergic diseases and asthma. However, functional characteristics of the EOS have been derived primarily from studies of blood cells, and it is unlikely that such assessments reflect events occurring in tissues or airways. To establish more precisely the function of airway EOS, segmental Ag challenge was used to elicit and isolate large numbers of these cells. Airway, as well as blood, EOS were isolated from allergic patients 48 h after segmental Ag challenge. Both blood and bronchoalveolar lavage (BAL) EOS were fractionated over Percoll density gradients; by using this protocol, three density-distinct populations of pure (>90%) EOS were obtained from BAL fluid (1.100, 1.095, and 1.090 g/ml) and one from blood (1.100 g/ml). The functions of these various populations were compared by measuring superoxide generation, adherence to collagen and endothelial cell monolayers, cell surface receptors, and in vitro survival. BAL EOS of all three densities had greater superoxide generation and adherence with FMLP activation than did corresponding blood EOS. In contrast, blood and airway EOS responded similarly to PMA. BAL EOS also had increased expression of CD11b/CD18 and HLA-DR. The intracellular calcium concentration ([Ca2+]i) was measured with the fluorescent marker indo-1/acetoxymethyl ester. FMLP caused a greater and more sustained increase in [Ca2+]i with BAL than blood EOS. EGTA blocked the sustained component of the [Ca2+]i response to FMLP. Our findings indicate that BAL EOS have an enhanced [Ca2+]i response to activation that may contribute to their functional up-regulation.

Adult↗
PubMed1992

Inhibition of eosinophil density change and leukotriene C4 generation by nedocromil sodium.

Nedocromil sodium (NS) has been shown to inhibit the late asthma response to inhaled antigen and to control symptoms in chronic asthma; in both processes the eosinophil is thought to be an important contributor. To understand the antiinflammatory actions of NS in asthma, its effects on three eosinophil functions were evaluated: (1) change in cell density during in vitro culture, (2) synthesis of leukotriene C4 (LTC4), and (3) generation of superoxide anion. In these studies normal density (greater than 1.095 gm/ml) purified human peripheral blood eosinophils were cultured for 24 hours in 50% conditioned medium from cow pulmonary arterial endothelial cells. After incubation, 45.2% +/- 8.0% of the eosinophils had a density less than 1.085 gm/ml. In the presence of NS (10 mumol/L), only 32.0% +/- 7.3% became less dense (p = 0.0393). In contrast, NS had no effect on changes in cell density after a 20-minute exposure of eosinophils to functional activators N-formyl-methionyl-leucyl-phenylalanine (0.1 mumol/L) or platelet activating factor (0.1 mumol/L). Furthermore, calcium ionophore-activated LTC4 secretion was found to be significantly inhibited by NS (3.8 +/- 0.6 ng/ml vs. 2.4 +/- 0.3 ng/ml with 1 mumol/L NS or 1.7 +/- 0.6 ng/ml with 10 mumol/L NS, p less than 0.025). However, NS did not significantly alter eosinophil superoxide anion generation. The effects of NS on eosinophil function suggest a mechanism by which this medication may be effective in asthma, particularly in the regulation of the late asthmatic response. Furthermore, the selective regulatory effects of NS may also provide insight into the biologic activities of eosinophils.

Adult↗
PubMed1992

Characteristics of peripheral blood eosinophils in patients with nocturnal asthma.

A number of mechanisms have been proposed to explain nocturnal exacerbations of asthma including circadian patterns in circulating cortisol and catecholamines. These factors may influence airway smooth muscle tone and circulating eosinophil characteristics and function. Because recent evidence has indicated that eosinophils contribute to airway inflammation and the severity of asthma, we evaluated the relationship among peripheral blood eosinophils, their density distribution, and the appearance of nocturnal asthma. Fifteen patients with asthma were evaluated. Spirometry (FEV1 and FVC) was determined at 0400 and 1600, and the number and density distribution of peripheral blood eosinophils were determined. Five patients had nocturnal asthma, defined as a 15% or greater fall in FEV1 at 0400 versus 1600. The patients with nocturnal asthma had greater numbers of eosinophils (cells x 10(6)/ml) at 0400 (0.845 +/- 0.13 versus 0.351 +/- 0.03) and 1600 (0.651 +/- 0.18 versus 0.319 +/- 0.07) and a greater circadian variation with peak eosinophilia at 0400. Furthermore, we found a significant circadian increase in low-density eosinophils (as determined by Percoll density gradient centrifugation) at 0400, but only in patients with nocturnal asthma. These observations suggest that a circadian variation in low density eosinophils may contribute to nocturnal exacerbations of asthma.

Adult↗
PubMed1992

Platelet-activating factor primes human eosinophil generation of superoxide.

Platelet-activating factor (PAF) is a potent inflammatory mediator that can cause airway obstruction and hyperresponsiveness; these processes are also associated with pulmonary eosinophilia, suggesting a link between these two events. Thus, PAF's interaction with eosinophils may provide a mechanism for airway damage. However, direct in vitro activation of eosinophils by PAF requires concentrations that are likely higher than those achieved in vivo. As a result, we investigated whether lower, more physiologic concentrations of PAF could prime eosinophils for subsequent activation to another receptor-stimulated factor, in this case formylmethionylleucylphenylalanine (FMLP). To test this hypothesis, eosinophils were preincubated (1 and 15 min) with low concentrations of PAF (1 x 10(-8) and 1 x 10(-10) M); this exposure to PAF resulted in enhanced generation of superoxide anion to FMLP stimulation. Moreover, similar concentrations of PAF decreased eosinophil density and increased expression of cell surface CR3 receptors. Finally, low, nonactivating concentrations of PAF (1 x 10(-10) to 1 x 10(-8) M) caused transient increases in eosinophil cytosolic free Ca2+ concentrations. Collectively, these responses are consistent with the hypothesis that short-term exposure to low concentrations of PAF primes eosinophils to cause an enhanced inflammatory response upon subsequent activation to another receptor agonist. The consequences of this PAF-associated phenomenon can produce an enhanced inflammatory response and airway injury.

Adult↗
PubMed1992

Eosinophils in asthma.

Eosinophils, a prominent feature of asthma, are found in increased numbers in the circulation and sputum, usually in relation to the severity of asthma. As a consequence of these clinical observations, investigators now speculate that the eosinophil has a central role in the pathogenesis of asthma. Recent evidence has begun to confirm these speculations. The allergic reaction of the airway to antigen and the development of the late asthmatic reaction have provided a clinical model to study asthma and the contribution of eosinophils to bronchial reactivity. In the late asthmatic reaction, airway eosinophilia occurs. Through a series of independent observations, the following eosinophil-related events have been noted with the development of late asthmatic reactions. With either laboratory or natural exposure to antigen, eosinophilic chemotactic factors are released. Although the sources of eosinophil chemotaxis are multicellular, this is an early step in the attraction of eosinophils to the airway. As this process is initiated, a series of events occurs to cause eosinophils to arrive in the airway and promote obstruction, injury, and bronchial hyperresponsiveness. These steps include eosinophil migration through the vascular endothelium, upregulation of eosinophils (characterized by a change in cell density), adhesion of eosinophils to airway epithelium, and release of eosinophil toxic products. This presentation will review some of the eosinophil-dependent factors that can cause asthma. Furthermore, the eosinophil may be a good target for future therapeutic interventions.

Animals↗
PubMed1991

The effect of platelet-activating factor on the generation of superoxide anion in human eosinophils and neutrophils.

The precise role of platelet-activating factor (PAF) in asthma has yet to be established. Nonetheless, the potential relationship between PAF and asthma appears to include the eosinophil (EOS) as an important link. Thus, to evaluate the effect of PAF on leukocyte-dependent inflammation, purified populations of human blood EOSs and neutrophils were isolated from the same subject. The two granulocyte populations were then incubated with PAF, and superoxide anion (O2-) generation was measured by reduction of cytochrome c in a microassay system. Both granulocyte cell types generated O2- when they were incubated with PAF. However, the generation of O2- was 3.4 times greater with EOSs (9.8 +/- 1.5 nmole of cytochrome c reduced per 5 x 10(5) cells) than neutrophils (2.9 +/- 0.4 nmole of cytochrome c reduced per 5 x 10(5) cells; p less than 0.0001). When the effect of PAF on [Ca++]i was measured with the fluorescent label, Indo-1, PAF caused similar increases in cellular fluorescence in both neutrophils and EOSs, but the increase in [Ca++]i of neutrophils occurred with lower concentrations of PAF. Furthermore, when similar experiments were conducted in the presence of an extracellular calcium chelator, ethylene glycol-bis-(beta-aminoethylether)-N,N,N',N'-tetraacetic acid, there was partial suppression in both the cellular fluorescence and O2- generation to PAF; this suggests that full expression of EOS generation of O2- by PAF requires both intracellular mobilization and a transmembrane influx of Ca++. Our data indicate that PAF can stimulate leukocyte O2- generation, but this response is greater in the EOS than the neutrophil. Therefore, our findings support the observation that the EOS is more responsive to PAF activation than other granulocytes and that this difference may contribute to participation of PAF in asthma.

Adult↗
PubMed1991

Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge. Characterization of eosinophil and mast cell mediators.

Segmental antigen bronchoprovocation was used to define the nature of the inflammatory process in allergic airway disease. Bronchoalveolar lavage fluid obtained from allergic rhinitis patients 12 min after segmental antigen instillation (immediate response) revealed a significant increase in histamine and tryptase, but no cellular response. Repeat segmental lavage 48 h later (late response) showed marked and significant increases in both low and normal density eosinophils as well as striking elevations of eosinophil granular protein levels (major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and eosinophil peroxidase). Leukotriene C4, but not tryptase, concentrations were also consistently elevated in late lavage samples. Further, the late lavage samples showed a significant increase in interleukin-5 concentrations that correlated with the presence of eosinophils and eosinophil granular proteins. Neither eosinophils nor soluble mediators of eosinophils increased when normal subjects were similarly challenged with antigen. These data suggest that eosinophils are attracted to the airway during the late-phase allergic reaction and that IL-5 may produce changes in airway eosinophil density and promote the release of granular proteins to cause airway injury.

Adult↗
PubMed1990

The appearance of hypodense eosinophils during interleukin-2 treatment.

Based on membrane receptors, metabolic activity, and cell density, human eosinophils (EOSs) are a heterogeneous population of leukocytes. EOS heterogeneity translates into biologic significance, since low density cells can be metabolically more active and thus more capable of causing tissue injury. Efforts to identify mechanisms that lead to the development of hypodense EOSs have found that an in vitro exposure to cytokines reduces cell density and is associated with increased cell activity. Consequently, we evaluated the effect of an in vivo administration of interleukin-2 (IL-2) on the cell counts and density of circulating EOSs in six patients who received IL-2 as cancer biologic-modifier therapy. To determine the pattern of EOS density in relationship to IL-2 treatment, granulocyte suspensions were isolated from peripheral blood and then centrifuged over multiple discontinuous density Percoll gradients. During IL-2 treatment, the percentage of circulating hypodense EOSs increased significantly (p less than 0.01) until nearly all (97.6 +/- 1.6%) EOSs were hypodense (density less than 1.095 gm/ml). Similarly, the absolute blood EOS counts significantly increased throughout treatment. On completion of IL-2 therapy, the EOS counts and density distribution returned to pretreatment values. In contrast, no increase in blood EOS counts was observed in similar patients receiving interferon (gamma or beta) therapy. Our observations support a hypothesis that IL-2, either directly or, more likely, through the generation of other factors, participates in a change in EOS density that may, in turn, establish a subpopulation of cells with altered metabolic activity.

Adult↗
PubMed1990

Superoxide generation by hypodense eosinophils from patients with asthma.

Low density, or hypodense eosinophils (HE) are found in increased numbers in asthma. Since HE have been reported to have increased inflammatory potential and correlate with the severity of airway obstruction, it has been suggested that this subpopulation of eosinophils may contribute to the asthma process. However, investigations to define the function of HE in asthma have been limited. In this study, pure populations of both HE and normal dense eosinophils were isolated from the peripheral blood of seven patients with asthma, and functional activity of these cells was determined by measuring superoxide (O2-) generation to several activators. Compared to normal dense eosinophils, HE generated significantly more O2- when activated with the chemotactic peptide FMLP or opsonized zymosan; however, these differences were small. In contrast, no difference was observed in O2- production between normal- and low-density eosinophils from asthma patients when stimulated by phorbol myristate acetate (PMA) or the calcium ionophore A23187. Furthermore, both eosinophil populations, and corresponding neutrophil isolates, from asthma patients generated significantly more O2- than control granulocytes when activated by PMA. When stimulated by calcium ionophore, all three eosinophil populations released equivalent amounts of O2-, which were, however, higher than from both neutrophil suspensions. Compared to increased activity found in some other hypereosinophilic conditions, blood HE in asthma do not necessarily have enhanced function. This suggests that eosinophil heterogeneity extends not only to cell density but is also reflected in cell function and that these cell variations are dependent on many factors, including the function assessed, source of cells (normal versus patients with some diseases), and stimulus used.

Adult↗
PubMed1989

The appearance of hypodense eosinophils in antigen-dependent late phase asthma.

Although peripheral blood eosinophils (EOS) of low density are increased in patients with asthma, the mechanisms contributing to their presence are not well established. The following study evaluated the effect of an antigen bronchoprovocation (BP) on the percentage of circulating hypodense eosinophils (HE) in asthma. EOS density was measured by centrifugation of peripheral blood granulocytes over multiple discontinuous density Percoll gradients in samples taken immediately before and 24 h after antigen BP. We found that the percentage of peripheral blood HE (density less than 1.095 g/ml) increased significantly (p less than 0.02) over baseline values (78.9 +/- 4.8% versus 53.3 +/- 8.2%, mean +/- SEM, n = 11) when evaluated 24 h after antigen BP but only in patients who experienced both an immediate (IAR) and late phase asthma reaction (LAR). No significant change in the percentage of HE was observed in asthma subjects who had only an early asthma response to inhaled antigen (n = 6). In an expanded population of allergic asthmatics (n = 38), a significant correlation was found between the percent peripheral blood HE and disease severity as represented by the percent predicted FEV1 (r = -0.56, p = 0.003). These data suggest that in vivo activation of asthma by inhaled antigen increases the proportion of peripheral blood EOS that are hypodense but only in those patients with both an IAR and LAR. Furthermore, we also conclude that the percentage of HE better reflects the severity of asthma than the concentration of total peripheral blood eosinophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Hypodense eosinophils in allergic rhinitis.

Based on density, function, and membrane receptors, peripheral blood eosinophils are a heterogeneous population of cells. Importantly, hypodense eosinophils (HE) are metabolically more active and likely to contribute to tissue injury. In the following study, peripheral blood from patients with allergic rhinitis (AR) was evaluated for the presence of HE. To accomplish this, blood was obtained from patients with ragweed AR, granulocytes were isolated and fractionated by continuous density Percoll gradients, and the density distribution of these cells was determined after centrifugation. A significantly higher percentage of peripheral blood eosinophils were hypodense (defined as density less than 1.081 gm/ml) in patients with AR when these patients were compared to control subjects, 30.0 +/- 5.0% versus 9.0 +/- 1.9%, p less than 0.01. Moreover, we also noted that an increased percentage of HE was found more often in patients with moderate-to-severe AR than in subjects with none-to-mild disease (p less than 0.01). These data suggest that the appearance of HE in the circulation may relate to the development of allergic symptoms. Furthermore, our observations suggest that the HE, because of its enhanced metabolic activity and now its association with more symptomatic hay fever, may participate in the pathophysiology of AR.

Adult↗
PubMed1988

Stimulus-dependent differences in superoxide anion generation by normal human eosinophils and neutrophils.

The role of eosinophils in allergic and hypersensitivity diseases has yet to be fully established and remains limited by techniques to isolate the eosinophil in high purity. Consequently, most studies that evaluate and characterize eosinophil function are conducted with isolates from patients with hypereosinophilia. There is, however, evidence to suggest that isolates from such patients do not represent normal function. Now, with new techniques to isolate and purify eosinophils from normal subjects without eosinophilia, metabolic function of the normal eosinophil can be assessed. To accomplish this, granulocytes from healthy volunteers were separated by continuous density Percoll gradients into populations of purified eosinophils (90.3 +/- 1.9%) and neutrophils (98.2 +/- 0.4%). Superoxide (O2-) generation was measured with a microassay of superoxide dismutase-inhibitable cytochrome c reduction in response to several soluble and particulate agonists. Normal eosinophils generated significantly more O2- in response to either phorbol myristate acetate or calcium ionophore A23187 than their matched neutrophil fractions. In contrast, differences in granulocyte response to zymosan and chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine, were dependent on the presence of cytochalasin B (CB) in the reaction. N-formyl-methionyl-leucyl-phenylalanine-stimulated eosinophils generated less O2- in the absence of CB but similar amounts in the presence of CB, compared to neutrophils. Activation by zymosan in the presence of 10% autologous serum generated similar amounts of O2- in all the cell populations when CB was present; however, in the absence of CB, neutrophils produced less O2- when they were compared to eosinophils. Therefore, normal eosinophils respond differently to some activators, compared to neutrophils, and these differences may prove significant as the contribution of eosinophils to inflammation becomes established.

Adolescent↗
PubMed1985

Stimulus-dependent inhibition of superoxide generation by prostaglandins.

Infiltrating phagocytes generate superoxide anion (O2-) and prostaglandin (PG) at sites of inflammation. Thus PG-O2- interactions may be important to the initiation and control of inflammation. PGE1, PGE2, and PGD2 inhibit O2- generation (as measured by superoxide dismutase-inhibitable reduction of ferricytochrome c) in a dose-dependent manner (10(-6)-10(-9) M) when human peripheral blood polymorphonuclear leucocytes (PMN) are stimulated with 10(-7) M of the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP). These PG did not alter O2- generation when PMN were stimulated with 0.1 microgram/ml phorbol myristate acetate (PMA) or 1 mg/ml serum-treated zymosan (STZ). Increments of cyclic AMP (cAMP) (peak: fourfold) in PGE1, PGE2, and PGD2 treated PMN stimulated with PMA or STZ (in which O2- was not reduced) were similar to those in PG-treated PMN stimulated with FMLP (in which O2- was reduced markedly). High concentrations of theophylline and dibutyryl cAMP reduced FMLP and STZ stimulated O2- generation but had no effect on PMA stimulation, suggesting that the stimuli induce different sensitivities to the effects of cellular cAMP. PGF2 alpha had little effect on O2- generation or cAMP levels regardless of the stimulus. PGE1 did not inhibit binding of FML(3H)P to PMN and did not scavenge O2- anions. Therefore the effect of PG on O2- production is dependent on the specific stimulator and an increased concentration of cAMP in activated PMN is by itself not sufficient to limit O2- generation induced by all stimuli.

Alprostadil↗