Margareta Linden

Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis.

Accumulation of eosinophils in the airways is characteristic of allergic rhinitis and asthma. The tissue eosinophilia may involve both recruitment of mature eosinophils and proliferation of their progenitors. This study examines mature eosinophils (nasal and circulating), their circulating progenitors, and a potential role of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in stimulating these progenitors. Twelve subjects with a history of seasonal allergic rhinitis and positive skin prick test for birch pollen were studied during four periods: shortly before, in the early and intense phase, at the end, and well after the Swedish birch‐pollen season. Nasal mucosal and circulating eosinophils were examined in both nasal brushings and peripheral blood samples. Eosinophil/basophil progenitors were determined by counting colony‐forming units in nonadherent mononuclear blood‐cell cultures in methylcellulose at 14 days. The nasal mucosal cytokines GM‐CSF, interleukin (IL)‐1β, IL‐3, IL‐5, IL‐6, IL‐8, and RANTES were analyzed (ELISA) in nasal lavage (NAL) fluids. All patients developed severe symptoms of rhinitis at the height of the season, with increased numbers of eosinophils in the nasal mucosa (P<0.05) and in the circulation (P<0.05). At this time point, the number of circulating progenitors (P<0.05) and the NAL fluid level of GM‐CSF (P<0.05) were also increased. In contrast, there was no change in the NAL fluid levels of IL‐1β, IL‐3, IL‐6, or IL‐8. Neither IL‐5 nor RANTES could be detected in any of the NAL fluids. At the end of or after the season, there was no increase in nasal eosinophils or circulating eosinophils or progenitors (P>0.05). Ex vivo addition of GM‐CSF (10–100 U) increased the number of blood progenitors grown before (P<0.01) and after (P<0.05) the season, compared with during the season. The in vitro GM‐CSF responsiveness of progenitors may be related to whether or not these already have been stimulated endogenously by GM‐CSF. Taken together, our data thus suggest that GM‐CSF may play a role in vivo to increase production of eosinophilic progenitors in allergic airway disease.

Antioxidative properties of organotellurium compounds in cell systems

The protective/antioxidative properties of diaryl tellurides were demonstrated in cellular systems of increasing complexity. In the presence of glutathione, bis(4-hydroxyphenyl) telluride (1a), bis(4-aminophenyl) telluride (1d) and bis(2-carboxyphenyl) telluride (1h) reduced by more than 50% t-butyl hydroperoxide-induced cell death in lung fibroblast cultures at concentrations below 2 microM. Bis(2,6-dimethyl-4-hydroxyphenyl) telluride (2b) reduced by more than 50% leukocyte-mediated and phorbol-12-myristate-13-acetate-stimulated damage to Caco-2 cells at 0.1 microM concentration. As judged by their abilities to reduce formation of thiobarbituric acid reactive substances at concentrations close to 1 microM, diaryl tellurides 1a, 1d and 2b protected rat kidney tissue against oxidative damage caused by anoxia and reoxygenation. The organotellurium compounds also offered protection after systemic administration. In the presence of diaryl telluride 2b (0.1-1 microM), the ischemia/reperfusion-induced vascular permeability increase in the hamster cheek pouch was significantly reduced as compared with the control. Some of the most active organotellurium cell protectants were evaluated for their ability to inhibit formation of the inflammatory mediators leukotriene B4 and interleukin-1beta. An inhibitory effect on the secretion of these species was seen for compounds 1a and 2b at or above 10 microM concentrations. The protective effects of diaryl tellurides against t-butyl hydroperoxide-induced cell injury can be ascribed mainly to the peroxide-decomposing, glutathione peroxidase-like capacity of the compounds. The chain-breaking, electron- or hydrogen atom-donating ability of diaryl tellurides seems to be the main reason for their protection against leukocyte-mediated cell damage in Caco-2 cells and in the oxidatively challenged rat kidney and hamster cheek pouch.

Nasal cytokines in common cold and allergic rhinitis

Coronavirus‐induced common cold and allergen‐induced rhinitis are characterized by nasal mucosal exudation of bulk blood plasma. The mucosal exudation process involves ‘flooding’ of the lamina propria with plasma‐derived binding proteins and it is possible that subepithelial inflammatory cytokines and mediators may be moved by the exudate to the mucosal surface. In this study, we have analysed cytokine levels in nasal lavage (NAL) fluids from non‐allergic subjects inoculated with coronavirus (n= 20) and from subjects with allergic (birch pollen) rhinitis subjected to additional allergen challenge (samples were obtained 35min post challenge) in the laboratory (n= 10). Ten of the 20 inoculated subjects developed common cold and 10 remained healthy. Interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), IL‐4, and IL‐6 were analysed in unprocessed NAL fluids using immunoassays. The subjects who developed common cold had increased NAL fluid levels of IFNγ (P < 0.05) that correlated well with the symptoms (P < 0.001). IFNγ did not increase in subjects with allergic rhinitis. IL‐1β levels were similar in NAL fluids obtained from all inoculated subjects. In the subjects with allergic rhinitis NAL fluid levels of both IL‐1β and GM‐CSF were increased (P < 0.05). GM‐CSF was not detected in common cold. IL‐4 and IL‐6 were not detectable in any of the NAL fluids. The present cytokines may not only emanate from superficial mucosal cells. By aiding plasma exudation subepithelial cytokines may potentially also be retrieved on the mucosal surface. Our study provides original in vivo data supporting the notion that a TH‐1 profile of cytokines, notably IFNγ, is present in viral infection and further supporting the view that GM‐CSF is an important cytokine in allergic airways disease.

Mucosal output of eotaxin in allergic rhinitis and its attenuation by topical glucocorticosteroid treatment

Background Eotaxin is a chemokine that attracts and activates eosinophils. The present study examines the occurrence of eotaxin in nasal mucosal surface liquids in patients with seasonal allergic rhinitis without allergen exposure and during repeat allergen challenge with and without topical glucocorticosteroid treatment. The number of subepithelial eosinophils and mucosal outputs of bulk plasma (α2‐macroglobulin) and eosinophil cationic protein (ECP) are also examined.

The effects of β2‐adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes

1 The in vitro effects of the β2‐adrenoceptor agonists (1 × 10−9−10−5 m), terbutaline, salmeterol, and formoterol, on the release of inflammatory mediators, i.e. the eicosanoids leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) and the cytokine interleukin‐1β (IL‐1β), were assessed in cultures of human blood monocytes. For comparison, the effects of a 5‐lipoxygenase inhibitor, BW A4C (1 × 10−9−10−5 m), and a corticosteroid, budesonide (1 × 10−10−10−5 m) were also examined. Sotalol was used to investigate whether the actions of β2‐agonists were mediated through β‐adrenoceptors. 2 Terbutaline, like budesonide, had no significant effect on LTB4 release, whereas BW A4C (IC50 = 2 × 10−8 m) was a potent inhibitor. All concentrations of formoterol approximately halved the LTB4 secretion, whereas high concentrations (1 × 10−7−10−5 m) only, of salmeterol, inhibited release. Only salmeterol, at high concentrations (> 1 × 10−6 m), lowered the secretion of PGE2 in monocyte cultures. Formoterol and salmeterol reduced the secretion of IL‐1β only at the highest dose (1 × 10−5 m). In contrast, budesonide (≥ 1 × 10−9 m) was a potent suppressant of this secretion. 3 Treatment of monocyte cultures with sotalol (1 × 10−5 m) did not significantly antagonize the inhibitory effects of salmeterol and formoterol. These results suggest that the inhibitory action of these β2‐agonists on the release of eicosanoids or IL‐1β, is not mediated via β2‐adrenoceptors. 4 This study does not support a therapeutic importance of the anti‐release effects of β2‐agonists since high concentrations were generally required. Furthermore, the anti‐secretory action of β2‐agonists was distinct from that of corticosteroids.

Alpha2-macroglobulin and eosinophil cationic protein in the allergic airway mucosa in seasonal allergic rhinitis

As previously demonstrated in seasonal allergic rhinitis, increased microvascular permeability and eosinophil activation are key features of allergic airway inflammation. In the present study, the hypothesis that exudation of alpha2-macroglobulin may cause the appearance of eosinophil cationic protein (ECP) in the airway lumen was explored. Nasal lavages were carried out using the nasal pool device before and during the pollen season both at baseline and after histamine challenge in 10 children with allergic rhinitis. Nasal lavage fluid levels of alpha2-macroglobulin and ECP were determined. All patients experienced nasal symptoms of allergic rhinitis during the pollen season (p<0.01-0.05). Baseline nasal lavage fluid levels of alpha2-macroglobulin and ECP were increased during the season (p<0.01-0.05) and were found to be well correlated (p<0.0001). Histamine produced concentration-dependent plasma exudation before and during the pollen season, but it was only during the pollen season that this caused an increase in the lavage fluid levels of ECP (p<0.05). These data suggest that exudation of plasma and increased tissue levels and output of eosinophil cationic protein characterize nasal mucosal inflammation in children with seasonal allergic rhinitis. The plasma exudation process in part may account for lumenal entry of eosinophil cationic protein molecules that have been released in mucosal tissue compartments. A combination of induced exudation and nasal lavage may improve the yield of important markers of inflammation in studies of nasal diseases.

Allergen challenge-induced acute exudation of IL-8, ECP and alpha2-macroglobulin in human rhinovirus-induced common colds

Abstract Rhinovirus infections cause exacerbations of eosinophilic airway disease. The acute effects of allergen‐challenge on nasal interleukin‐8 (IL‐8), eosinophil cationic protein (ECP), and α2‐macroglobulin were examined in atopic subjects with common cold symptoms. Twenty‐three patients with seasonal allergic rhinitis were inoculated with human rhinovirus 16 outside the pollen season. Diluent and allergen challenges, followed by nasal lavages, were carried out about 3 months before and 4 days after virus inoculation. Seventeen patients developed significant common cold symptoms with increased nasal lavage fluid levels of α2‐macroglobulin, IL‐8, and ECP at baseline (p<0.001–0.05 versus before inoculation), and were further increased by allergen challenge (p<0.001–0.05); IL‐8 and ECP levels were correlated (r=0.63, p<0.001). Before inoculation, the six patients who later did not develop common cold symptoms had high levels of IL‐8 and myeloperoxidase (MPO), and exhibited strong allergen‐induced plasma exudation responses (α2‐macroglobulin). After inoculation, IL‐8 and ECP did not increase in these symptomless subjects. In conclusion, high nasal interleukin‐8 and myeloperoxidase levels and exudative hyperresponsiveness may protect against infection. The association between nasal interleukin‐8 and eosinophil cationic protein in common cold, particularly that observed in nasal lavage fluids after allergen‐induced acute exudation of plasma, suggests the involvement of interleukin‐8 in exacerbation of airway mucosal eosinophil activity.

Experimental common cold increases mucosal output of eotaxin in atopic individuals

Background: In view of recent observations demonstrating that rhinovirus infections are associated with increased local activity of eosinophils, we hypothesized that eotaxin, a selective eosinophil chemoattractant, may be involved in eosinophil recruitment/activation in common cold infections.