Sudden-Onset Fatal Asthma: A Distinct Entity with Few Eosinophils and Relatively More Neutrophils in the Airway Submucosa?

Sur, Sanjiv; Crotty, Thomas B.; Kephart, Gail M.; Hyma, Bruce A.; Colby, Thomas V.; Reed, Charles E.; Hunt, Loren W.; Gleich, Gerald J.

doi:10.1164/ajrccm/148.3.713

Cited by 554 publications

(341 citation statements)

References 21 publications

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“…It is possible that the increased numbers of eosinophils in the cases of fatal asthma is due to factors related not only to severity but also to a final episode of asthma. SUR et al [20] have shown that cell profiles in the airway wall may be temporally related to a fatal attack of asthma, and we have recently confirmed these findings [39]. In both studies, neutrophils were observed in much smaller numbers than lymphocytes and eosinophils in cases of fatal asthma, and may be important in the pathogenesis of a fatal attack of asthma.…”

Section: Discussionsupporting

confidence: 82%

“…In cases of fatal asthma, the numbers of eosinophils were more closely related to the number of lymphocytes than in the nonfatal asthma and control cases. Numerous studies [3,12,15,16,19,20,24,[32][33][34] have shown increased numbers both of lymphocytes and eosinophils in asthmatic airways, although not over the range of asthma severity and airway sizes sampled in this study. It has been suggested that cell/ endothelial adhesion mechanisms and chemoattractant cytokines [35][36][37][38] may provide a common pathway of extravasation for lymphocytes and eosinophils at sites of inflammation.…”

Section: Discussionmentioning

confidence: 52%

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The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

Carroll

Cooke²,

James³

1997

Eur Respir J

246

163

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Airway inflammation in asthma consists of variably increased numbers of mononuclear and polymorphonuclear cells, and there is a growing body of evidence to suggest a primary role for lymphocytes and eosinophils in the pathogenesis of asthma. The aim of this study was to examine the distribution of lymphocytes and eosinophils in the bronchial tree of cases of mild and severe asthma.In cases of fatal asthma (n=10), nonfatal asthma (sudden nonrespiratory death with a history of asthma n=10), and control cases (sudden death with no history of respiratory illness, n=10), lymphocytes and eosinophils were counted in transverse sections of large and small airways stained with haematoxylin and eosin.Cases of fatal asthma had longstanding severe asthma and nonfatal cases generally had mild asthma. Lymphocytes were increased in all airway size groups both in fatal and nonfatal cases of asthma compared to control cases (p<0.001). Eosinophils were increased (p<0.001) in all airway size groups in the cases of fatal asthma compared to the nonfatal asthma and control groups, which were similar. These differences between case groups were of similar magnitude, when only a random single airway section from each case in each size group was examined. The numbers of lymphocytes correlated with the number of eosinophils in the fatal asthma group (r=0.60; p<0.0001), and to a lesser extent in the nonfatal (r=0.34; p=0.001) and control groups (r=0.32; p=0.001).These findings suggest that increased numbers of lymphocytes are uniformly distributed in the large and small airways in cases of asthma, independently of asthma severity, and that eosinophil recruitment may be related to asthma severity. Hence, biopsy specimens of the proximal airways are likely to be representative of the cellular infiltrate in large and small airways in mild and severe asthma.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 52%

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

Carroll

Cooke²,

James³

1997

Eur Respir J

246

163

View full text Add to dashboard Cite

show abstract

“…The asthmatic inflammatory response consists of infiltration into the airway of a variety of activated inflammatory cells with release of mediators of asthma pathophysiology. The eosinophil has an established role as an effector cell in asthma but the pro-inflammatory role of other granulocytes, in particular the neutrophil, remains less well defined [1,2].Increased numbers of airway neutrophils have been described in severe steroid-dependent asthma, during acute exacerbations and in cases of sudden-onset fatal disease [3][4][5]. An increase in neutrophil activation, but not numbers, in mild chronic asthma has previously been shown [6].…”

mentioning

confidence: 99%

“…Increased numbers of airway neutrophils have been described in severe steroid-dependent asthma, during acute exacerbations and in cases of sudden-onset fatal disease [3][4][5]. An increase in neutrophil activation, but not numbers, in mild chronic asthma has previously been shown [6].…”

mentioning

confidence: 99%

Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthmain vivo

Reid¹,

Ward²,

Wang³

et al. 2003

Eur Respir J

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In-vitro data suggest that long-acting b 2 -agonists may have a neutrophilstabilising effect. A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described. There is currently interest in the "neutrophil system" in asthma, and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8, neutrophils and myeloperoxidase (MPO) in persistent asthma.In the same 12-week double-blind parallel-group placebo-controlled study as described previously, the effects on bronchoalveolar lavage fluid (BALF) IL-8, neutrophils and MPO of introducing salmeterol (50 mg b.i.d.) or giving additional inhaled corticosteroid (fluticasone 100 mg b.i.d.) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated.At baseline, BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls. MPO levels correlated strongly with IL-8 levels, and weakly with BALF neutrophil numbers in the asthmatics. Fluticasone treatment resulted in significantly elevated neutrophil numbers, but not MPO or IL-8 levels. In contrast, introducing salmeterol significantly reduced IL-8 and MPO levels, but did not affect BALF neutrophil numbers. Interestingly, salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils, and there was a divergent effect on IL-8 levels that almost reached significance.Excessive interleukin-8 levels may be relevant to asthma pathogenesis, even in the setting of moderate-dose inhaled corticosteroid therapy. Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting b 2 -agonist rather than merely increasing inhaled corticosteroid doses. Indeed, high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia. Asthma is characterised by airway inflammation, bronchial hyperresponsiveness and reversible airflow obstruction. The asthmatic inflammatory response consists of infiltration into the airway of a variety of activated inflammatory cells with release of mediators of asthma pathophysiology. The eosinophil has an established role as an effector cell in asthma but the pro-inflammatory role of other granulocytes, in particular the neutrophil, remains less well defined [1,2].Increased numbers of airway neutrophils have been described in severe steroid-dependent asthma, during acute exacerbations and in cases of sudden-onset fatal disease [3][4][5]. An increase in neutrophil activation, but not numbers, in mild chronic asthma has previously been shown [6]. The role of airway neutrophils in the pathogenesis of persistent asthma despite mild/moderate inhaled corticosteroid (ICS) doses has not been established. However, more recent data confirm considerable heterogeneity of the asthma phenotype and many subjects may exhibit an airway disease characterised by sputu...

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“…In addition, neutrophils are a predominant leukocyte present upon histopathologic postmortem examinations of airways of patients with fatal asthma (6,7), and they produce several proinflammatory mediators such as cytokines, proteases, oxygen metabolites, and prostanoids (8). Our understanding of the mechanisms regulating the trafficking of neutrophils to the lungs during Ag-induced inflammation is poor.…”

mentioning

confidence: 99%

Rapid Up-Regulation of CXC Chemokines in the Airways after Ag-Specific CD4+ T Cell Activation

Knott

Gater

Dunford

et al. 2001

The Journal of Immunology

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Ag-specific activation of CD4+ T cells is known to be causative for the cytokine production associated with lung allergy. Chemokine-induced leukocyte recruitment potentially represents a critical early event in Ag-induced lung inflammation. Whether Ag-specific, lung CD4+ T cell activation is important in lung chemokine production is currently not clear. Using αβ-TCR transgenic BALB/c DO11.10 mice, we investigated the ability of Ag-specific CD4+ T cell activation to induce lung chemokine production and leukocyte recruitment. Within 1 h of exposure of DO11.10 mice to OVA aerosol, lung mRNA and protein for the neutrophil chemokines KC and macrophage inflammatory protein (MIP)-2 were greatly increased. Accordingly, neutrophils in the airways increased by >50-fold, and KC and MIP-2 proved to be functional because their neutralization significantly reduced airway neutrophilia. CD4+ T cell activation was critical because CD4+ but not CD8+ T cell depletion reduced KC production, which correlated well with the previously observed inhibition of neutrophil influx after CD4+ T cell depletion. In vitro studies confirmed that OVA-induced KC and MIP-2 production was conditional upon the interaction of CD4+ T cells with APCs. A likely secondary mediator was TNF-α, and a probable source of these chemokines in the lung was alveolar macrophages. Thus, Ag-specific CD4+ T cell activation in the lung leads to rapid up-regulation of neutrophil chemokines and the recruitment of neutrophils to the site of Ag exposure. This may be a key early event in the pathogenesis of Ag-induced lung inflammation.

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Sudden-Onset Fatal Asthma: A Distinct Entity with Few Eosinophils and Relatively More Neutrophils in the Airway Submucosa?

Cited by 554 publications

References 21 publications

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics

Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthmain vivo

Rapid Up-Regulation of CXC Chemokines in the Airways after Ag-Specific CD4+ T Cell Activation

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