Airway Goblet Cell Hyperplasia Research Articles

Beyond our pages

Beyond our pages

Viral induction of a chronic asthma phenotype and genetic segregation from the acute response.

Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short- and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-gamma deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma.

Il-13 and IFN-gamma: interactions in lung inflammation.

Chronic inflammatory diseases of the lungs, such as asthma, are frequently associated with mixed (Th2 and Th1) T cell responses. We examined the impact of critical Th1 and Th2 cytokines, IFN-gamma and IL-13, on the responses in the lungs. In a mouse model of airway inflammation induced by mixed T cell responses, the number of Th1 (IFN-gamma-positive) cells was found to be negatively correlated with airway hyperreactivity. In these mice, blockade of IL-13 partially inhibited airway hyperreactivity and goblet cell hyperplasia but not inflammation. In contrast, in mice that responded with a polarized Th2 response to the same Ag, blockade of IL-13 inhibited airway hyperreactivity, goblet cell hyperplasia, and airway inflammation. These results indicated that the presence of IFN-gamma would modulate the effects of IL-13 in the lungs. To test this hypothesis, wild-type mice were given recombinant cytokines intranasally. IFN-gamma inhibited IL-13-induced goblet cell hyperplasia and airway eosinophilia. At the same time, IFN-gamma and IL-13 potentiated each other's effects. In the airways of mice given IL-13 and IFN-gamma, levels of IL-6 were increased as well as numbers of NK cells and of CD11c-positive cells expressing MHC class II and high levels of CD86. In conclusion, IFN-gamma has double-sided effects (inhibiting some, potentiating others) on IL-13-induced changes in the lungs. This may be the reason for the ambiguous role of Th1 responses on Th2 response-induced lung injury.

Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.

Excessive airway mucus is an important cause of morbidity and mortality in asthma, but the relationship between accumulation of mucus and goblet cell size, number, and function is incompletely understood. To address these questions, stored mucin in the epithelium and goblet cell size and number were measured morphometrically, and mucin gene expression was measured by polymerase chain reaction and immunohistochemistry in endobronchial biopsies from 13 subjects with mild and moderate asthma and from 12 healthy control subjects. Secreted mucin was measured in induced sputum. We found that stored mucin in the airway epithelium was three times higher than normal in the subjects with asthma (p < 0.005). Goblet cell size was similar in both groups, but goblet cell number was significantly higher in the subjects with asthma (93,043 +/- 15,824 versus 41,959 +/- 9,230/mm3, p < 0.05). In mild asthma (FEV1 > or = 80% pred, n = 7), the level of stored mucin was as high as in moderate asthma (FEV1 < 80% pred, n = 6), but the level of secreted mucin was significantly lower (28.4 +/- 6.3 versus 73.5 +/- 47.5 microg/ml, p < 0.05). Secreted mucin was inversely correlated with stored mucin for the whole asthma group (rs = -0.78, p = 0.007). MUC5AC was the predominant mucin gene expressed in healthy subjects and subjects with asthma, and MUC5AC protein was increased in the subjects with asthma. We conclude that even mild asthma is associated with goblet cell hyperplasia and increased stored mucin in the airway epithelium, whereas moderate asthma is associated with increased stored mucin and secreted mucin. These findings suggest that acute degranulation of hyperplastic goblet cells may represent a mechanism for asthma exacerbations in mild and moderate asthma and that chronic degranulation of goblet cells may contribute to chronic airway narrowing in moderate asthma.

Recurrent milk aspiration produces changes in airway mechanics, lung eosinophilia, and goblet cell hyperplasia in a murine model.

Recurrent aspiration of milk into the respiratory tract has been implicated in the pathogenesis of a variety of inflammatory lung disorders including asthma. However, the lack of animal models of aspiration-induced lung injury has limited our knowledge of the pathophysiological characteristics of this disorder. This study was designed to evaluate the effects of recurrent milk aspiration on airway mechanics and lung cells in a murine model. Under light anesthesia, BALB/c mice received daily intranasal instillations of whole cow's milk (n = 7) or sterile physiologic saline (n = 9) for 10 d. Respiratory system resistance (Rrs) and dynamic elastance (Edyn,rs) were measured in anesthetized, tracheotomized, paralyzed and mechanically ventilated mice 24 h after the last aspiration of milk. Rrs and Edyn,rs were derived from transrespiratory and plethysmographic pressure signals. In addition, airway responses to increasing concentrations of i.v. methacholine (Mch) were determined. Airway responses were measured in terms of PD(100) (dose of Mch causing 100% increase from baseline Rrs) and Rrs,max (% increase from baseline at the maximal plateau response) and expressed as % control (mean +/- SE). We found recurrent milk aspiration did not affect Edyn and baseline Rrs values. However, airway responses to Mch were increased after milk aspiration when compared with control mice. These changes in airway mechanics were associated with an increased percentage of lymphocytes and eosinophils in the bronchoalveolar lavage, mucus production, and lung inflammation. Our findings suggest that recurrent milk aspiration leads to alterations in airway function, lung eosinophilia, and goblet cell hyperplasia in a murine model.

Goblet Cell Hyperplasia in the Airway of Nippostrongylus brasiliensis-Infected Rats

Background: In rats, the intestinal parasite Nippostrongylus brasiliensis is recognized as a strong inducer of intestinal goblet cell hyperplasia. Although this parasite migrates through the airways during the course of its infection, airway goblet cell response remains unknown. Objective: This study was designed to examine airway goblet cell response during the course of N. brasiliensis infection in rats and to characterize these goblet cells. Methods: Airway goblet cells were stained with Alcian blue and periodic acid-Schiff. To characterize the goblet cells, mebendazole treatment, lectin histochemistry, and RNA blot analysis using probes for rat MUC2 and trefoil peptides were examined. Results: Airway and small intestinal goblet cell hyperplasia were observed at days 14 and 21 after infection but not at day 7. In rats treated with mebendazole, goblet cell hyperplasia was not present in the small intestine, but was observed in the lung on day 14. These results indicate that airway goblet cell hyperplasia may be induced by local pulmonary factors. By lectin histochemistry, the stainability of airway goblet cells at day 21 was similar to that of small intestine goblet cells even though rat MUC2 and trefoil peptide mRNA were not detected in the lung. Conclusions: Airway goblet cell hyperplasia observed at days 14 and 21 after N. brasiliensis infection may be induced by local factors. Airway goblet cells have characteristics that differ from those of the small intestine.

Pollution and the immune response: atopic diseases--are we too dirty or too clean?

The effect of pollutants on the immune system has filled tomes and is almost always controversial whether the topic is disinfectants in drinking water or particulates and lung cancer. Even whether outdoor and indoor air quality is improving or declining has been a source of considerable investigation, consultation and often litigation. Few areas, however, yield so much uncertainty and debate as the role of airborne pollutants in atopy. Atopy is defined as an immunoglobulin E- (IgE) mediated allergic response to environmental antigens and can be manifested as rhinitis, asthma or atopic dermatitis. While there is some debate over whether there has been a real increase in atopy over the last decades, it is indisputable that there has been a dramatic change over the last 200 years. While isolated cases of anaphylaxis had been noted before, allergies were unheard of until the early 19th century. Only 54 years after the first description of hay fever in England in 1819, it was considered an epidemic and a clear association with urbanization had been reported.1 What aspect of urbanization is involved has been much debated. There has been much discussion amongst both experimental immunologists and epidemiologists over whether pollutants are responsible for increased allergic sensitization and/or severity.2,3 In the last few years new studies have supported an alternative explanation, namely the decline in infectious diseases in industrialized countries.4,5 Does this ‘hygiene theory’ toll the death knell for the ‘pollution theory’? In this review I will argue that there is a compelling case to be made for both theories and that even this is not the entire picture.

Chronic Airway Hyperreactivity, Goblet Cell Hyperplasia, and Peribronchial Fibrosis during Allergic Airway Disease Induced by Aspergillus fumigatus

Clinical allergic airway disease is associated with persistent airway hyperreactivity and remodeling, but little is known about the mechanisms leading to these alterations. This paucity of information is related in part to the absence of chronic models of allergic airway disease. Herein we describe a model of persistent airway hyperreactivity, goblet cell hyperplasia, and subepithelial fibrosis that is initiated by the intratracheal introduction of Aspergillus fumigatus spores or conidia into the airways of mice previously sensitized to A. fumigatus. Similar persistent airway alterations were not observed in nonsensitized mice challenged with A. fumigatus conidia alone. A. fumigatus-sensitized mice exhibited significantly enhanced airway hyperresponsiveness to a methacholine challenge that was still present at 30 days after the conidia challenge. Eosinophils and lymphocytes were present in bronchoalveolar lavage (BAL) samples from A. fumigatus-sensitized mice at all times after conidia challenge. Compared with levels measured in A. fumigatus-sensitized mice immediately before conidia, significantly elevated interferon-gamma (IFN-gamma) and transforming growth factor (TGF-beta) levels were present in whole lung homogenates up to 7 days after the conidia challenge. At day 30 after conidia challenge, significantly elevated levels of interleukin-4 (IL-4) and IL-13 were present in the A. fumigatus-sensitized mice. Histological analysis revealed profound goblet cell hyperplasia and airway fibrosis at days 30 after conidia, and the latter finding was confirmed by hydroxyproline measurements. Thus the introduction of A. fumigatus conidia into A. fumigatus-sensitized mice results in persistent airway hyperresponsiveness, fibrosis, and goblet cell hyperplasia.

The Effect of dexamethasone on airway goblet cell hyperplasia and inflammation in TiO2-treated sprague-dawley rats

Backgrounds : The pathophysiology of chronic airflow obstruction, such as bronchial asthma, is characterized by mucus hypersecretion, goblet cell hyperplasia(GCH), smooth muscle hypertrophy, and inflammatory cells infiltration. In fatal asthma patients, one distinct findings is mucus hypersecretion due to GCH. However, the mechanisms of GCH in these hypersecretory diseases remain still unknown. In this study, a rat model was rapidly induced with GCH by instillation of , intratracheally. We intend to confirm GCH and association of concomitant inflammatory cells infiltration and to observe the effect of potent antiinflammatory agent, that is dexamethasone, on GCH with inflammatory cells. Methods : Twenty-one 8-weeks-old male Sprague-Dawley rats were divided into three groups. Endotoxinfree water was instilled intratracheally in group 1(control) ; , was instilled in the group 2 ; and dexamethasone was injected intraperitoneally to group 3 before instillation. After 120 hours, all rats were sacrificed, and trachea, bronchi, and lungs were resected respectively. These tissues were made as paraffin blocks and stained as PAS for goblet cells and Luna stain for eosinophils. We calculated the ratio of goblet cell to respiratory epithelium and number of infiltrated eosinophils from each tissue. Results : (1) Fraction of goblet cells was significantly increased in group 2 than in group 1 in the trachea and in the main bronchus. (10.1911.33% vs 4.098.28%, p23.91% vs 3.614.84%, p3.84% vs 0.170.47 in trachea and 47.7116.91 vs 2.711.96 in main bronchi). (3) There was a positive correlation between goblet cells and eosinophils(r=0.719, p=0.001). (4) There was significant difference in the decrease of goblet cells after dexamethasone injection between group 2 and group 3 (p-induced goblet cell hyperplasia. GCH was observed mainly in the main bronchi with concomitant eosinophilic infiltration. Both goblet cell hyperplasia and eosinophilic infiltration were suppressed by dexamethasone. This animal model may serve as a useful tool in understanding of the mechanism of GCH in chronic airway diseases.

Model systems for investigating mucin gene expression in airway diseases.

Overproduction of mucus and of mucin glycoproteins and goblet cell hyperplasia occurs in chronic obstructive airway diseases, including asthma and cystic fibrosis. Mucus overproduction results from alterations in several cellular processes, including altered regulation of airway mucin genes on exposure to environmental and infectious agents and to inflammatory mediators. Seven of the nine identified MUC genes (which encode the protein backbone of mucins) are normally expressed in human respiratory tract tissues. Several inflammatory mediators have now been shown to regulate expression of MUC2, MUC5AC, and MUC5B genes. Importantly, mucin gene expression can be regulated both transcriptionally and posttranscriptionally. Current information on airway mucin gene expression is summarized in this review along with an overview of airway epithelial model systems. In vitro model systems include airway epithelial carcinoma cell lines and primary normal human bronchial epithelial (NHBE) cells. In vivo systems include human respiratory tract tissues and rodent airways. Our laboratory has begun to investigate the role of cytokines on mucin gene expression in vitro and in vivo and on goblet cell metaplasia in vivo. Because cytokines can alter cell proliferation, we characterized the effect of interleukin (IL)-4 and IL-13 on the proliferation of NHBE cells and three human lung carcinoma cell lines--A549, NCI-H292, and Calu-3--that are frequently used for analyses of airway mucin gene expression. Both IL-4 and IL-13 had cell-specific effects. They increased proliferation moderately (1.2-3.0-fold) in NHBE and Calu-3 cells, but markedly inhibited proliferation of A549 cells in a dose-dependent manner. IL-4 increased proliferation of NCI-H292 cells moderately, although IL-13 had no significant effect. We also examined the role of IL-13 and IL-4 on MUC5AC messenger RNA (mRNA) expression in A549, Calu-3, and H292 cell lines and did not observe any significant effect. However, we recently showed an increase in Muc-5ac mRNA and protein expression in a murine model of ovalbumin-induced allergic asthma and in murine airways when IL-13 was delivered intranasally (Alimam, N.Z., et al. Am J. Respir. Cell Mol. Biol. 22:253--260). Thus, we speculate that IL-13 plays a role in the differentiation of murine airway epithelial cells into goblet cells, which then express Muc-5ac mRNA. A detailed analysis of the role of cytokines in airway cell differentiation and mucin gene expression both in vitro and in vivo is required to elucidate the roles of mucins in airway health and diseases. Identification of Muc-5ac as a major gene and gene product in goblet cell metaplasia should facilitate delineation of the molecular mechanisms underlying the induction and reversal of airway goblet cell metaplasia and goblet cell hyperplasia.

Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone.

We recently described a murine model of atopic asthma in which a marked, extensive hyperplasia of airway goblet cells is induced by repeated challenge of ovalbumin (OA)-sensitized mice with intratracheally administered allergen (Am. J. Respir. Cell Mol. Biol. 1996;14:425-438). We report here the time course of the duration of this feature and of its spontaneous resolution in the absence of further allergen exposure. Induction of severe neutrophilic inflammation in the airways by repeated intratracheal administration of lipopolysaccharide failed to induce goblet cell hyperplasia (GCH) to as great a degree as that induced by allergen, suggesting that nonallergic inflammation is a relatively poor inducer of this phenotype change in mice. When a "subclinical" infection of the lungs with the human A2 strain of respiratory syncytial virus was superimposed on the model of atopic asthma, recruitment of monocytes and lymphocytes to the airways was enhanced and a discharge of goblet cell mucin contents was observed. This may partly explain the respiratory difficulty that typifies virally induced exacerbations of asthma in humans. Daily systemic treatment of sensitized mice with dexamethasone during the period of allergen challenge produced a dose-related suppression of developing GCH, while similar treatment during the period following the establishment of extensive hyperplasia induced an accelerated resolution toward a normal epithelial phenotype. These results confirm and extend the relevance of this model as a representation of the human disease.

Induction of the Muc-5/5ac Mucin Gene in a Murine Model of Asthma ♦ 1963

Several studies have shown that respiratory challenge with ovalbumin of mice previously sensitized to this protein causes pulmonary pathology similar to that seen in human asthma, including airway goblet cell hyperplasia which is thought to be caused by upregulation of mucin genes. A recent study of transgenic mice that overexpress murine interleukin-4 in airway cells demonstrated goblet cell hyperplasia in association with pulmonary expression of the Muc-5/5ac but not of the Muc-2 mucin gene. The purpose of this study was to determine which airway mucin genes are involved in the goblet cell hyperplasia seen in mice sensitized and challenged with ovalbumin. Balb/C mice were sensitized (days 0, 4, 7, 11, 14) and challenged (days 25, 26, 27) with ovalbumin (100 micrograms, in saline) (Group A), and studied 24 hours after the last challenge (day 28). Control mice (Group B) were given saline alone. Histological analysis of the lungs revealed a striking lymphocyte and eosinophil inflammatory infiltrate in the interstitium of the bronchovascular bundle and prominent airway goblet cell hyperplasia in Group A but not in Group B mice. Northern analysis of lung RNA demonstrated expression of the Muc-5/5ac gene in Group A but not in group B mice, and expression of the Muc-1 gene in mice from both groups. Our findings demonstrate that pulmonary expression of the Muc-5/5ac mucin gene is associated with airway goblet cell hyperplasia in the ovalbumin murine model of asthma.

気管支ぜん息と気道過敏性の発症機序 薬理学的展開 気道分泌こう進と粘液線毛輸送障害

Mucociliary transport function can be determined by ciliary motility of airway epithelial cells, the amount and physicochemical properties of airway surface fluid, and the airway integrity. Mucus glycoprotein is released from submucosal glands and goblet cells in response to a variety of stimuli and, on other hand, water is secreted by airway epithelial cells through the movement of electrolytes. Marked airway goblet cell hyperplasia has been found in patients who died of severe asthma, indicating that goblet cell hypersecretion may play a significant role in the formation of mucus plugs in the respiratory tract. Goblet cell secretion is regulated by autonomic nerves and various chemical mediators associated with asthma. Antigen challenge causes an increase in mucus discharge from goblet cells in ovalbumin-sensitized animals, and this effect can be greatly inhibited by an histamine H2-receptor antagonist. Similarly, histamine released by antigen challenge stimulates airway epithelial Cl secretion and, hence, water secretion toward the airway lumen. There is ample evidence that mucociliary clearance is impaired in patients with asthma, which results in deterioration of airflow limitation. The precise mechanism for this impairment remains uncertain, but bronchospasm and the increased mucus secretion induced by peptide leukotrienes may be involved.

Loss of Cilia and Altered Phenotypic Expression of Ciliated Cells After Acute Sulfur Dioxide Exposure

Prolonged exposure of animals to sulfur dioxide (300 to 500 ppm) is known to result in airway goblet cell hyperplasia, and therefore, has been used as a model for long-term bronchitis. Relatively little is known about the acute effects of sulfur dioxide on airway epithelium. The purpose of this study was to characterize the effect of a single 3-h exposure to sulfur dioxide (500 ppm) on tracheal epithelium of weanling ferrets.