Changes in Bone Marrow Inflammatory Cell Progenitors after Inhaled Allergen in Asthmatic Subjects

Wood, Lorna J.; Inman, Mark D.; Watson, Richard M.; Foley, Ronan; Denburg, Judah A.; O’Byrne, Paul M.

doi:10.1164/ajrccm.157.1.9704125

Cited by 128 publications

(105 citation statements)

References 28 publications

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“…Furthermore, in humans this receptor also seems to be up-regulated by allergen exposure in asthmatics developing a late asthmatic reaction (15). This is in parallel with increased number of CFUs producing eosinophils in bone marrow samples taken after allergen exposure (24). Thus, allergen exposure seems to have slightly different regulatory effects in the bone marrow of allergic mice and asthmatic patients, although the models are similar in some respects because bone marrow activation can be observed in both species (24, 13-15, 20, 24).…”

Section: Discussionmentioning

confidence: 94%

Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

Tomaki

Zhao

Lundahl

et al. 2000

The Journal of Immunology

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The airway inflammation in asthma is dominated by eosinophils. The aim of this study was to elucidate the contribution of newly produced eosinophils in airway allergic inflammation and to determine mechanisms of any enhanced eosinophilopoiesis. OVA-sensitized BALB/c mice were repeatedly exposed to allergen via airway route. Newly produced cells were identified using a thymidine analog, 5-bromo-2′-deoxyuridine, which is incorporated into DNA during mitosis. Identification of IL-5-producing cells in the bone marrow was performed using FACS. Bone marrow CD3+ cells were enriched to evaluate IL-5-protein release in vitro. Anti-IL-5-treatment (TRFK-5) was given either systemically or directly to the airways. IL-5R-bearing cells were localized by immunocytochemistry. Repeated airway allergen exposure caused prominent airway eosinophilia after three to five exposures, and increased the number of immature eosinophils in the bone marrow. Up to 78% of bronchoalveolar lavage (BAL) granulocytes were 5-bromo-2′-deoxyuridine positive. After three allergen exposures, both CD3+ and non-CD3 cells acquired from the bone marrow expressed and released IL-5-protein. Anti-IL-5 given i.p. inhibited both bone marrow and airway eosinophilia. Intranasal administration of anti-IL-5 also reduced BAL eosinophilia, partly via local effects in the airways. Bone marrow cells, but not BAL eosinophils, displayed stainable amounts of the IL-5R α-chain. We conclude that the bone marrow is activated by airway allergen exposure, and that newly produced eosinophils contribute to a substantial degree to the airway eosinophilia induced by allergen. Airway allergen exposure increases the number of cells expressing IL-5-protein in the bone marrow. The bone marrow, as well as the lung, are possible targets for anti-IL-5-treatment.

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Section: Discussionmentioning

confidence: 94%

Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

Tomaki

Zhao

Lundahl

et al. 2000

The Journal of Immunology

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“…Previous studies in human and mouse systems have shown that local allergen exposure results in enhanced eosinophilopoiesis in BM. This prominently contributes to local eosinophilia, possibly via a feedback mechanism existing between the local tissue and BM, which triggers allergic inflammatory reaction [32][33][34]. Recent studies have shown that eosinophil precursors in BM are identifiable as CD34 + /IL-5R § + cells [35].…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells from Chlamydia‐infected mice show altered Toll‐like receptor expression and play a crucial role in inhibition of allergic responses to ovalbumin

et al. 2004

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Our previous study has shown that Chlamydia lung infection can inhibit local eosinophilic inflammation induced by allergen sensitization and challenge, which is correlated with altered cytokine production. In the present study, we examined the role played by dendritic cells (DC) in chlamydial infection-mediated modulation of allergic responses. The results showed that DC freshly isolated from Chlamydia-infected mice (iIDC), unlike those from naive control mice (iNDC), could efficiently modulate immune responses to ovalbumin in vitro and in vivo. Co-culture of freshly isolated DC with naive CD4 cells from T cell receptor transgenic mice (DO11.10) showed that iIDC directed Th1-dominant, while iNDC directed Th2-dominant, allergen-specific CD4 T cell responses. Moreover, adoptive transfer of iIDC, but not iNDC, could inhibit systemic and local eosinophilia induced by allergen exposure. The reduction of eosinophilia was associated with a decrease in IL-5 receptor expression on bone marrow cells and the production of IL-5 and IL-13 by T lymphocytes. Analysis of the DC showed that iIDC expressed significantly higher levels of mRNA for Toll-like receptor 9 and produced more IL-12 compared to iNDC. The data demonstrate a critical role played by DC in infection-mediated inhibition of allergic responses.

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“…Apart from changes in the bone marrow in asthmatic patients (Wood et al 1998), changes have also been found in the intestinal mucosa (Wallaert et al 1995). Studies on intestinal permeability by means of Cr-EDTA, demonstrated increased intestinal permeability by asthmatic patients as compared to healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

Sjöswärd¹,

Josefsson²,

Ahlner³

et al. 2003

Pharmacology & Toxicology

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Patients with asthma are a target group for medication with b2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries b2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 mg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R-and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons PϽ0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.Racemic R,S salbutamol is used to relieve bronchial constriction, the b2-agonist effect being mediated by the Renantiomer. S-Salbutamol may also have a pharmacological effect, but distinctly different from that of R-salbutamol. In vitro experiments have indicated increased production of histamine in mast cells following S-salbutamol (Cho et al. 2001) and furthermore, increase of intracellular Ca 2π by muscarinic receptor activation has been shown in connection with the S-enantiomer (Mitra et al. 1998). The latter effect may be a possible link to enhanced bronchial hyperresponsiveness, suggested to occur after regular treatment with salbutamol in asthmatic patients, and suspected to be associated with the presence of S-salbutamol (Nelson 1999).Previous studies have shown a distinct stereoselective metabolism. Both R-and S-enantiomers are metabolised by sulfotransferases, mainly in the gut and liver (Walle et al. 1996);(Hartman et al. 1998) to inactive metabolites. Sulfotransferases work more effectively with the R-enantiomer, hence the bioavailability of S-isomer by far exceeds that of the R-enantiomer, resulting in S-to R-salbutamol ratio in plasma exceeding one after administration to human beings. Racemisation in the stomach accounts for a small degree (6%) of interconversion (Boulton & Fawcett 2001).Although a limited number of pharmacokinetic studies has been performed in asthmatic patients, most pharmacokinetic studies have been conducted on healthy volunteers. It seems more appropriate though, to study a target popula-

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Changes in Bone Marrow Inflammatory Cell Progenitors after Inhaled Allergen in Asthmatic Subjects

Cited by 128 publications

References 28 publications

Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

Dendritic cells from Chlamydia‐infected mice show altered Toll‐like receptor expression and play a crucial role in inhibition of allergic responses to ovalbumin

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

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