Aggregations of Lymphoid Cells in the Airways of Nonsmokers, Smokers, and Subjects with Asthma

Elliot, John; Jensen, Cathryn M.; Mutavdzic, Slavko; Lamb, Jasmine; Carroll, Neil; James, Alan

doi:10.1164/rccm.200308-1167oc

Cited by 68 publications

(60 citation statements)

References 43 publications

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“…Previous reports have implicated the receptor for epidermal growth factor (EGFR) 1 in the induction of mucin gene MUC5AC by smoke (9). Consistent with a role for EGFR in mucin induction, an EGF response element has been identified 200 bp upstream of the MUC5AC gene (14).…”

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confidence: 68%

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Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Gensch

Gallup

Sucher

et al. 2004

Journal of Biological Chemistry

142

120

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In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFRindependent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK.The primary cause of morbidity in chronic bronchitis is mucin overproduction, a phenomenon for which the molecular pathogenesis is unknown. Inflammatory cells are abundant in smokers' airways (1-3) and are capable of stimulating mucin production (4 -7), suggesting that at least some of the excessive mucin in smokers' lungs is secondary to inflammation.In addition, however, smoke itself can induce mucin synthesis in lung cells (8,9). The question of how this occurs is complex in that smoke, a composite of irritant molecules including acetaldehyde, hydroquinone, formaldehyde, benzo-[a]pyrene, cresol, nicotine, catechol, acrolein, coumarin, anthracene, nitrogen oxides, and heavy metals (10, 11) may act on lung epithelial cells in diverse ways. For example, the induction of cytochrome P450 by tobacco smoke (12) is mediated by binding of the aryl hydrocarbon nuclear receptor to a dioxin response element in the 5Ј-flank of the gene, but the induction of the ␥-glutamylcysteine synthetase heavy subunit (␥-GCS-HS) gene is mediated by the binding of a c-Jun/c-Jun homodimer to an AP-1-like response element (13).Previous reports have implicated the receptor for epidermal growth factor (EGFR) 1 in the induction of mucin gene MUC5AC by smoke (9). Consistent with a role for EGFR in mucin induction, an EGF response element has been identified 200 bp upstream of the MUC5AC gene (14). The response of this element to EGFR ligands EGF and transforming growth factor-␣ is mediated by Sp1. One might predict from these data that the induction of MUC5AC by smoke would depend on interaction between the EGF response element at Ϫ200 bp and Sp1.In contrast, in the present study we show that MUC5AC is controlled principally by a smoke response element ϳ3 kb upstream of the EGF response element. This element is AP-1-dependent and is bound by Ju...

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confidence: 68%

“…Inflammatory cells are abundant in smokers' airways (1)(2)(3) and are capable of stimulating mucin production (4 -7), suggesting that at least some of the excessive mucin in smokers' lungs is secondary to inflammation.…”

mentioning

confidence: 99%

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Gensch

Gallup

Sucher

et al. 2004

Journal of Biological Chemistry

142

120

View full text Add to dashboard Cite

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“…Therefore, the potential for interaction of these two APC types within both RT compartments may profoundly affect local humoral and cellular immunity. Indeed, lymphoid follicles containing B cells have been shown to be present in the airways under pathological conditions, such as asthma and exposure to tobacco smoke (44), and were associated with airway wall inflammation and remodeling.…”

Section: Discussionmentioning

confidence: 99%

Anatomical Location Determines the Distribution and Function of Dendritic Cells and Other APCs in the Respiratory Tract

Garnier

Filgueira

Wikström

et al. 2005

The Journal of Immunology

224

240

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APCs, including dendritic cells (DC), are central to Ag surveillance in the respiratory tract (RT). Research in this area is dominated by mouse studies on purportedly representative RT-APC populations derived from whole-lung digests, comprising mainly parenchymal tissue. Our recent rat studies identified major functional differences between DC populations from airway mucosal vs parenchymal tissue, thus seriously questioning the validity of this approach. We addressed this issue for the first time in the mouse by separately characterizing RT-APC populations from these two different RT compartments. CD11chigh myeloid DC (mDC) and B cells were common to both locations, whereas a short-lived CD11cneg mDC was unique to airway mucosa and long-lived CD11chigh macrophage and rapid-turnover multipotential precursor populations were predominantly confined to the lung parenchyma. Airway mucosal mDC were more endocytic and presented peptide to naive CD4+ T cells more efficiently than their lung counterparts. However, mDC from neither site could present whole protein without further maturation in vitro, or following trafficking to lymph nodes in vivo, indicating a novel mechanism whereby RT-DC function is regulated at the level of protein processing but not peptide loading for naive T cell activation.

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“…For example, the density of neutrophils and activated eosinophils in the submucosa is not only much less than that of mast cells [6,8], but their density relative to that of mast cells appears to vary according to sub-compartments, such as mucous glands [34] and airway smooth muscle [50]. Lymphocyte numbers are much higher in the airway wall [6,24] and their density is subject to much greater variability [51]. Furthermore, the mast cell appears to be by far the predominant inflammatory cell within the layer of smooth muscle [52].…”

Section: Generalisability Of the Findingsmentioning

confidence: 99%

Do bronchial biopsies represent mast cell density in airways? A stereological study

Carroll

Carroll²

2006

European Respiratory Journal

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Endobronchial biopsy specimens may not adequately represent inflammatory cell counts throughout the airway wall. The present study aimed to compare mast cell density in biopsies and airway sections using both stereological and nonstereological methods.Post mortem biopsies and adjacent transverse sections were obtained from a mean of five proximal airways per case in 10 subjects who had died of nonrespiratory causes. Tryptasepositive mast cells were measured stereologically in 30-mm sections and nonstereologically in 5-mm sections using an optical disector (cells?mm ), respectively. Reference areas included the inner and total airway wall and to 100 mm below the basement membrane.Case means, based on four or more biopsy sites, significantly correlated with those on transverse sections for counts over the inner airway wall only, using both stereological and nonstereological methods. Cells?mm -3 and cells?mm -2 were significantly correlated within all reference areas. When endobronchial biopsies are obtained from at least four proximal airways per case, intersubject comparisons of mean mast cell density in the inner airway wall are as well represented by counts on biopsies as they are on transverse sections. This is the case using either threedimensional, stereological or two-dimensional, nonstereological methods.

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Aggregations of Lymphoid Cells in the Airways of Nonsmokers, Smokers, and Subjects with Asthma

Cited by 68 publications

References 43 publications

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

Anatomical Location Determines the Distribution and Function of Dendritic Cells and Other APCs in the Respiratory Tract

Do bronchial biopsies represent mast cell density in airways? A stereological study

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