Induced Trefoil Factor Family 1 Expression by Trans-Differentiating Clara Cells in a Murine Asthma Model

Kouznetsova, Irina; Chwieralski, Caroline E.; Bälder, Ralf; Hinz, Manfred; Braun, Armin; Krug, Norbert; Hoffmann, Werner

doi:10.1165/rcmb.2006-0008oc

Cited by 42 publications

(46 citation statements)

References 74 publications

(70 reference statements)

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“…These data suggest that Muc5b is sufficient for the homeostatic functions of airway mucus, whereas the expression of Muc5ac may take on greater importance under pathophysiological conditions. Numerous studies from our group and others focused on the association of the up-regulated production of mucin in disease states such as asthma (13,14), chronic obstructive pulmonary disease (15-17), and cystic fibrosis (18)(19)(20), and in animal models of these diseases (7,(21)(22)(23)(24)(25)(26). In the present study, however, we focused on the production of airway mucins under nondiseased conditions.…”

Section: Discussionmentioning

confidence: 95%

Mucin Production during Prenatal and Postnatal Murine Lung Development

Roy

Rahmani

Hernández

et al. 2011

American Journal of Respiratory Cell and Molecular Biology

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Mucus is a protective gel that lines respiratory tract surfaces. To identify potential roles for secreted gel-forming mucins in lung development, we isolated murine lungs on embryonic days (E) 12.5-18.5, and postnatal days (PN) days 5, 14, and 28. We measured the mucin gene expression by quantitative RT-PCR, and localization by histochemical and immunohistochemical labeling. Alcian blue/periodic acid-Schiff-positive cells are present from E15.5 through PN28. Muc5b transcripts were abundant at all time points from E14.5 to PN28. By contrast, transcript levels of Muc5ac and Muc2 were approximately 300 and 85,000 times lower, respectively. These data are supported by immunohistochemical studies demonstrating the production and localization of Muc5ac and Muc5b protein. This study indicates that mucin production is prominent in developing murine lungs and that Muc5b is an early, abundant, and persistent marker of bronchial airway secretory cells, thereby implicating it as an intrinsic component of homeostatic mucosal defense in the lungs. At approximately 4 weeks of gestation in humans (embryonic days 9.0-9.5 in mice), tracheal and lung-bud formation initiates as a pocket of endoderm evaginates from the ventral floor of the embryonic foregut and invades the underlying mesoderm. The developing lungs undergo repeated branching steps, giving rise to the complex of tubes that form the conducting airways and alveolar saccules. During this process of branching and morphogenesis, the endoderm changes from an undifferentiated mass to a pseudostratified squamous layer, and then to a differentiated layer comprised of heterogeneous progenitor and mature cells (1).Mature respiratory epithelial cells possess many unique functions that can be attributed to their structural features or their secretory products. Structural features such as the long, apical projections of tracheobronchial ciliated cells and the thin sheet-like squamous morphologies of alveolar Type I cells are examples of obvious morphological traits that are specifically linked to cellular function (ciliary clearance and gas exchange, respectively). Secreted products also demarcate the functions of individual respiratory epithelial subtypes. The tracheobronchial epithelium produces secreted products, such as mucins, that serve defensive functions by preventing the accumulation of particles and pathogens in the distal lung (2-4), whereas Type II pneumocytes produce surfactant lipids that reduce surface tension and prevent alveolar collapse, thereby permitting effective gas exchange (5). Additional anatomically selective markers include the secretaglobin (Scgb) family, with members such as Scgb1a1 (or Clara cell secretory protein) in the airways, and surfactant proteins A, B, and C in the alveoli. The expression of many of these markers is low early during lung development, when the bronchial epithelium is poorly differentiated, and becomes more abundant as epithelial maturation occurs late in embryonic gestation and throughout postnatal life (6).The importance of muc...

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Section: Discussionmentioning

confidence: 95%

Mucin Production during Prenatal and Postnatal Murine Lung Development

Roy

Rahmani

Hernández

et al. 2011

American Journal of Respiratory Cell and Molecular Biology

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“…These cells can be greatly expanded upon exposure to environmental agents, such as allergens or cigarette smoke. Although the origin of the goblet cells is still little understood, there is increasing evidence that they arise from Clara cells, basal cells or an undifferentiated progenitor cell (Alessandrini et al, 2010;Chen et al, 2009;Evans et al, 2004;Hayashi et al, 2004;Kouznetsova et al, 2007;Morrisey and Hogan, 2010;Reader et al, 2003;Roy et al, 2011;Turner and Jones, 2009) A previous study shows that antigen challenge in ovalbumin-sensitized adult mouse elicits mucin production in Clara cells in the intrapulmonary airways (Evans et al, 2004). Another study shows that in the same model the increase in number of…”

Section: Discussionmentioning

confidence: 99%

Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development

Tsao

Wei

et al. 2011

Development

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Goblet cell metaplasia and mucus overproduction contribute to the pathogenesis of chronic lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notch signaling regulates cell fate decisions and is crucial in controlling goblet cell differentiation in the gut epithelium. Little is known, however, about how endogenous Notch signaling influences the goblet cell differentiation program that takes place in the postnatal lung. Using a combination of genetic and in vitro approaches here we provide evidence of a novel role for Notch in restricting goblet cell differentiation in the airway epithelium during the postnatal period. Conditional inactivation of the essential Notch pathway component Pofut1 (protein O-fucosyltransferase1) in Tgfb3-Cre-expressing mice resulted in an aberrant postnatal airway phenotype characterized by marked goblet cell metaplasia, decreased Clara cell number and increase in ciliated cells. The presence of the same phenotype in mice in which the Notch transcriptional effector Rbpjk was deleted indicated the involvement of the canonical Notch pathway. Lineage study in vivo suggested that goblet cells originated from a subpopulation of Clara cells largely present in proximal airways in which Notch was disrupted. The phenotype was confirmed by a panel of goblet cell markers, showed no changes in cell proliferation or altered expression of proinflammatory cytokines and was associated with significant downregulation of the bHLH transcriptional repressor Hes5. Luciferase reporter analysis suggested that Notch directly repressed MUC5AC transcription in lung epithelial cells. The data suggested that during postnatal life Notch is required to prevent Clara cells from differentiating into goblet cells.

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“…IL-13 induces not only MUC5AC gene expression leading to mucin synthesis, a defining characteristic of the goblet cell phenotype, but also induces other genes, some of which are important for goblet cell function, including the genes for the CaCC1, and the trefoil factor family (TFF),which will be mentioned later [34,35]. In addition, Young et al [36] indicated that up-regulated Muc5AC expression is the central event in goblet cell metaplasia in antigen-challenged mice.…”

Section: Goblet Cell Metaplasia From Clara and Ciliated Cellsmentioning

confidence: 99%

Molecular Mechanisms of Metaplasia, Differentiation and Hyperplasia of Goblet Cellin Allergic Asthma

Hayashi¹

2012

J Aller Ther

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Bronchial allergic asthma (asthma) is an airway inflammation characterized by airflow obstruction of variable degrees with bronchial hyper-responsiveness and is induced by a complex interaction of environmental and genetic factors. Asthma of the human can be divided into an immediate-and a late-phase reaction, and some of the patients develop a late-phase reaction after a symptom-free interval. Hallmarks of asthma are mucus overproduction by goblet cells associated with responses of helper T(Th)2 cells. Mucus hypersecretion from goblet cells themselves or by metaplasia and/or hyperplasia of goblet cells appears to be associated with disease severity in asthma, because mucus production by those cells in local bronchial-bronchiolar lesions causes airway mucus plugging. However, the mechanisms of mucus production are not fully understood. Molecular mechanisms of goblet cell metaplasia, differentiation and hyperplasia will be reviewed in this article. Also, the relationship between allergic inflammation in Th1/Th2 paradigm shift and thymic stromal lymphopoietin (TSLP) was included for the understanding of goblet cell response in asthma. The clarification of mechanisms of mucin production in vivo may lead to the development of novel therapeutic strategies to suppress mucus production in asthma.

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Induced Trefoil Factor Family 1 Expression by Trans-Differentiating Clara Cells in a Murine Asthma Model

Cited by 42 publications

References 74 publications

Mucin Production during Prenatal and Postnatal Murine Lung Development

Mucin Production during Prenatal and Postnatal Murine Lung Development

Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development

Molecular Mechanisms of Metaplasia, Differentiation and Hyperplasia of Goblet Cellin Allergic Asthma

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