Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways.
ABSTRACT Interleukin (IL)-13 induces important features of bronchial asthma such as eosinophilic infiltration, airway hyperresponsiveness (AHR), and mucus hypersecretion. Although glucocorticoids suppress airway inflammation and remain the most effective therapy for asthma, the effects of glucocorticoids on the IL-13-dependent features are unknown. We studied the effects of dexamethasone on eotaxin production, eosinophil accumulation, goblet cell hyperplasia, and AHR after IL-13 administration into the airways of mice in vivo. MUC5AC gene expression, a marker of goblet cell hyperplasia, was also analyzed. IL-13 alone dose dependently induced AHR. Treatment with dexamethasone inhibited eotaxin expression and completely abolished eosinophil accumulation, but it did not affect AHR, MUC5AC overexpression, or goblet cell hyperplasia induced by IL-13. The effects of tumor necrosis factor-alpha on IL-13-induced AHR were also examined. Tumor necrosis factor-alpha did not affect AHR despite marked enhancement of eosinophil infiltration in IL-13-treated mice. These findings suggest that glucocorticoid is not sufficient to suppress IL-13-induced AHR or goblet cell hyperplasia and that eotaxin expression and eosinophilic inflammation do not have a causal relationship to the induction of AHR or goblet cell hyperplasia by IL-13. Control of steroid-resistant features induced by IL-13, including AHR and mucus production, may provide new therapeutic modalities for asthma.
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ABSTRACT: IL-13, a helper T-cell type2 (Th2) cytokine transforms cultured airway epithelial cells to goblet cells and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described. We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signaling pathways associated with IL-33 activation in these cells. NHBE cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 hours. CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (p<0.01) and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells but not from normally differentiated cells (p<0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (p<0.05) and PD98059, a MAPK/ERK kinase inhibitor attenuated IL-33 stimulated CXCL8/IL-8 secretion from goblet cells (p<0.001). IL-13 induced ST2 mRNA (p<0.02) and membrane bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (p<0.02). Goblet cells secrete CXCL8/IL-8 and this is increased by IL-33 through ST2R-ERK pathway suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia. This article is protected by copyright. All rights reserved.Clinical & Experimental Allergy 01/2014; · 4.79 Impact Factor
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ABSTRACT: Bronchiolar Clara cells play a critical role in lung homoeostasis. The main goal of this study was to evaluate the effects of chronic allergy on these cells and the efficacy of budesonide (BUD) and montelukast (MK) in restoring their typical phenotypes after ovalbumin-induced chronic allergy in mice. Chronic allergy induced extensive bronchiolar Alcian blue-periodic acid-Schiff (AB/PAS)-positive metaplasia. In addition, cells accumulated numerous big electron-lucent granules negative for Clara cell main secretory protein (CC16), and consequently, CC16 was significantly reduced in bronchoalveolar lavage. A concomitant reduction in SP-D and CYP2E1 content was observed. The phenotypic changes induced by allergy were pharmacologically reversed by both treatments; MK was more efficient than BUD in doing so. MK decreased AB/PAS reactivity to control levels whereas they remained persistently elevated after BUD. Moreover, most non-ciliated cells recovered their normal morphology after MK, whereas for BUD normal cells coexisted with 'transitional' cells that contained remnant mucous granules and stained strongly for CC16 and SP-D. Glucocorticoids were also less able to reduce inflammatory infiltration and maintained higher percentage of neutrophils, which may have contributed to prolonged mucin expression. These results show that chronic allergy-induced mucous metaplasia of Clara cells affects their defensive mechanisms. However, anti-inflammatory treatments were able to re-establish the normal phenotype of Clara cell, with MK being more efficient at restoring a normal profile than BUD. This study highlights the role of epithelial cells in lung injuries and their contribution to anti-inflammatory therapies.International Journal of Experimental Pathology 09/2013; · 2.04 Impact Factor
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ABSTRACT: Inhaled glucocorticoid dexamethasone is the most effective treatment of asthma currently available. Epithelial damage and shedding represents a clear manifestation of asthmatic pathologies. However it remains unknown if dexamethasone regulates functions of airway progenitor cells that are responsible for epithelial repair. In present study Secretoglobin1a1 (Scgb1a1) lineage tracing mice were injected intraperitoneally with tamoxifen to induce the expression of green fluorescence protein (GFP) in Scgb1a1-expressing conducting airway progenitor cells. Scgb1a1-expressing progenitor cells were isolated from lungs of Scgb1a1 lineage tracing mice via flow activated cell sorting. In vitro three-dimensional matrigel culture of these progenitor cells revealed that dexamethasone has little effect on the colony forming ability of airway epithelial progenitor cells, but exhibits significant effects on the differentiation of the progenitor cells. Compared to the untreated group, dexamethasone treatment inhibited the expression of forkhead box J1 (FoxJ1) and mucin subtype A & C (Muc5Ac), but promoted the expression of calcium activated chloride channel 3 (Clca3) and cystic fibrosis transmembrane conductance regulator (Cftr). Dexamethasone-induced effects on the expression of FoxJ1, Muc5Ac and Clca3 were abolished or even reversed in the presence of RU486, an antagonist of glucocorticoid receptor, indicating that glucocorticoid receptor plays a role in the regulation of airway epithelial progenitor cells by dexamethasone. These data suggested that, though effective to reduce airway inflammation, dexamethasone treatment alone fails to fully restore the mucociliary clearance function in the treatment of asthma patients.Steroids 12/2013; · 2.80 Impact Factor