A Model of Airway Narrowing in Asthma and in Chronic Obstructive Pulmonary Disease

Wiggs, Barry; Bosken, Carol H.; Paré, Peter D.; James, Alan; Hogg, James C.

doi:10.1164/ajrccm/145.6.1251

Cited by 410 publications

(266 citation statements)

References 11 publications

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“…These results extend the findings from previous studies using endobronchial biopsies by showing that a similar but more severe inflammatory process is present in the peripheral airways and in the airway wall external to the smooth muscle layer-both of which are not routinely biopsied during fibreoptic bronchoscopy. This data is consistent with the evidence that suggests that the small airways are the major site of obstruction in asthma (Macklem et al 1970, Wiggs et al 1992, Kuwano et al 1993). In addition, the extensive presence of inflammatory cells throughout the airways makes it possible that these cells may be important modulators of the function of other cells present in airway tissues-including epithelial cells, fibroblasts and smooth muscle cells.…”

Section: Asthma and Allergic Inflammationsupporting

confidence: 92%

IL-5 and IL-5 receptor in asthma

Kotsimbos

Hamid

1997

Mem. Inst. Oswaldo Cruz

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and a soluble isoform (αIL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1 and STAT 5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD 4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of αIL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased

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Section: Asthma and Allergic Inflammationsupporting

confidence: 92%

IL-5 and IL-5 receptor in asthma

Kotsimbos

Hamid

1997

Mem. Inst. Oswaldo Cruz

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“…As morphometric studies are not available in humans for technical reasons, little is known about this aspect of steroid-mediated activity in human subjects. Mathematical models underline the importance of airway wall thickness in the pathogenesis of AHR [34]. In the study by SONT et al [12], it was shown that adapting the dose of ICS not only to control symptoms and baseline lung function, but in addition to decrease AHR, resulted in a reduction of the degree of subepithelial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats

Vanacker¹,

Palmans²,

Pauwels³

et al. 2002

European Respiratory Journal

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To examine whether fluticasone propionate (FP) dose-dependently inhibits inflammatory as well as structural changes, Brown Norway rats were sensitised to ovalbumin (OA) on day 0 and 7. From day 14-28, rats were exposed to aerosolised OA (1%) or phosphate buffered saline every 2 days. Thirty minutes before each allergen exposure, animals were pre-treated with aerosolised placebo or FP (0.1, 1 or 10 mg) or prednisolone 3 mg?kg -1 i.p.At day 29, 0.1 mg FP had no measurable effect, either on inflammatory or structural changes, such as goblet cell hyperplasia and airway wall thickening. The allergeninduced increase in eosinophilic inflammation in bronchoalveolar lavage fluid and in the airway mucosa, as well as increased fibronectin deposition, were inhibited by treatment with FP from a dose of 1 mg onwards. Inhibition of goblet cell hyperplasia and thickening of the airway wall required 10 mg inhaled FP. At this dose, systemic effects were observed. However, for a comparable degree of systemic activity, prednisolone was far less effective at preventing airway changes.The dose of inhaled fluticasone propionate required to inhibit allergen-induced structural alterations was higher than to prevent eosinophil influx, and caused systemic side-effects. However, for a similar systemic activity, prednisolone was ineffective in preventing airway remodelling.

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“…To predict the effect of airway dimensions on airway resistance, a computational model, as described by WIGGS et al [22] and modified by LAMBERT et al [23], was used. Briefly, the geometry of the bronchial tree in the model is a dichotomously branching network with 16 generations.…”

Section: Airway Dimensions and Computational Model For Airway Resistancementioning

confidence: 99%

Cartilaginous airway wall dimensions and airway resistance in cystic fibrosis lungs

Tiddens¹,

Koopman²,

Lambert³

et al. 2000

Eur Respir J

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It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model.Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance.The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3-and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients.The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients. Eur Respir J 2000; 15: 735±742.

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A Model of Airway Narrowing in Asthma and in Chronic Obstructive Pulmonary Disease

Cited by 410 publications

References 11 publications

IL-5 and IL-5 receptor in asthma

IL-5 and IL-5 receptor in asthma

Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats

Cartilaginous airway wall dimensions and airway resistance in cystic fibrosis lungs

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