Conditional Depletion of Airway Progenitor Cells Induces Peribronchiolar Fibrosis

Perl, Anne‐Karina T.; Riethmacher, Dieter; Whitsett, Jeffrey A.

doi:10.1164/rccm.201005-0744oc

Cited by 71 publications

(58 citation statements)

References 53 publications

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“…More definitive evidence for this concept comes from experiments in which Clara cells were ablated in adult mice by inducible expression of a diphtheria toxin transgene. Transgene induction for 10 days led to extensive Clara cell loss, and airway fibrosis was observed when lungs were examined 19 wk later (29). A similar phenomenon was observed in chlorine-exposed FVB/NJ mice, in which airways that had a poorly repaired epithelium developed fibrosis.…”

Section: Discussionmentioning

confidence: 55%

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

Chen

Schlueter

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Mo Y, Chen J, Schlueter CF, Hoyle GW. Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis. Am J Physiol Lung Cell Mol Physiol 304: L92-L102, 2013. First published November 21, 2012 doi:10.1152/ajplung.00272.2012.-Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated. acute lung injury; airway hyperreactivity; basal cells CHLORINE IS A WIDELY USED industrial chemical and is one the top ten chemicals produced by gross weight (9). Chlorine gas is considered a chemical threat agent and is a highly toxic respiratory irritant that when inhaled causes cellular injury, alveolar-capillary barrier disruption, inflammation, pulmonary edema, and, at very high levels of exposure, death (9,21,39,44). Human exposure to chlorine has occurred from both intentional and accidental releases of chlorine (9,17,33,41,43). Humans exposed to high levels of chlorine develop acute lung injury, but most individuals recover from these acute effects (17, 43). However, additional follow-up studies suggest the existence of a subset of exposed individuals who experience chronic impairment of pulmonary function, which may include airway hyperreactivity, airway obstruction, or decreased residual volumes (1,18,23,33). Long-term effects of chlorine inhalation have been studied in the context of acute irritant-induced asthma (2, 23). Patients who developed irritant-induced asthma as a result of chemical exposure (most commonly chlorine) had evidence of airway obstruction, fibrosis, and hyper...

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Section: Discussionmentioning

confidence: 55%

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

Chen

Schlueter

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Tracing the lineage of bronchiolar Clara cells demonstrated that the airway and alveolar epithelia comprise distinct lineages in the steady state (11). Although injury may lead to bronchiolarization of the alveolar duct or alveolarization of the terminal bronchiole (12)(13)(14), the roles for a dual-lineage cell, termed the bronchoalveolar stem cell, (13) have been challenged (9,15). The molecular mechanisms that establish these lineages have received intense scrutiny, and b-catenin was identified as one player in this process.…”

Section: Lung Epithelial Cell Lineagesmentioning

confidence: 99%

“…Although such models are extremely useful, they must be interpreted in the context of extensive epithelial damage and the potential involvement of other cell and tissue types. Consequently, identification of low-level tracheal epithelial damage (i.e., decreased nuclear Vv/Sv) in the BiTg model allowed us the uncommon opportunity to evaluate the roles of b-catenin under conditions of less severe injury, and to compare these results with those in other models of low-level injury (15,54).…”

Section: Roles For B-catenin-dependent Gene Injury and Repairmentioning

confidence: 99%

Roles for β-Catenin and Doxycycline in the Regulation of Respiratory Epithelial Cell Frequency and Function

Smith¹,

Hicks²,

Reynolds³

2012

Am J Respir Cell Mol Biol

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The expression of b-catenin-dependent genes can be increased through the Cre recombinase (Cre)-mediated elimination of the exon 3-encoded sequence. This mutant b-catenin is termed DE3, and promotes the expression of b-catenin-dependent genes. Our previous study used the DE3 model to demonstrate that persistent b-catenin activity inhibited bronchiolar Clara-to-ciliated cell differentiation. The present study was designed to evaluate the roles of b-catenin in regulating the tracheal progenitor cell hierarchy. However, initial experiments demonstrated that the tetracyclineresponsive element-Cre transgene (TRE-Cre) was active in the absence of a reverse tetracycline transactivator driver or inducer, doxycycline (Dox). This spurious TRE-Cre transgene activity was not detected using the ROSA26-floxed STOP-LacZ reporter. To determine if the phenotype was a consequence of genotype or treatment with Dox, tracheal and lung specimens were evaluated using quantitative histomorphometric techniques. Analyses of uninduced mice demonstrated a significant effect of genotype on tracheal epithelial cell mass, involving basal, Clara-like cell types. The bronchial and bronchiolar Clara cell mass was also decreased. Paradoxically, an effect on ciliated cell mass was not detected. Activation of the b-catenin reporter transgene TOPGal demonstrated that b-catenin-dependent gene expression led to the genotype-dependent tracheal and bronchiolar phenotype. Comparative analyses of wild-type or keratin 14-rtTA1/1 mice receiving standard or Dox chow demonstrated an effect of treatment with Dox on basal, Clara-like, and Clara cell masses. We discuss these results in terms of cautionary notes and with regard to alterations of progenitor cell hierarchies in response to low-level injury.Keywords: Clara cell; doxycycline; Cre recombinase; b-catenin; stereology LUNG EPITHELIAL CELL LINEAGESThe tracheobronchial, bronchiolar, and alveolar compartments of murine airway epithelia contain distinct cell lineages. Within the tracheobronchial compartment, basal cells act as progenitors of secretory and ciliated cells during lung development (1). However, Clara-like cells are the progenitors of ciliated cells in the adult steady-state trachea (2). After treatment with naphthalene (NA), the basal cell becomes the progenitor of nascent Clara-like and ciliated cells (3-7). We suggested that signaling from Clara-like cells to basal cells limits the fate of adult basal cells to self-renewal (3).The bronchiolar epithelium is maintained by Clara cells (8, 9), whereas the alveolar epithelium is maintained by Type II cells (10). Tracing the lineage of bronchiolar Clara cells demonstrated that the airway and alveolar epithelia comprise distinct lineages in the steady state (11). Although injury may lead to bronchiolarization of the alveolar duct or alveolarization of the terminal bronchiole (12-14), the roles for a dual-lineage cell, termed the bronchoalveolar stem cell, (13) have been challenged (9, 15). The molecular mechanisms that establish these lineages have re...

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“…This study illustrates a key role for the alveolar epithelium in the modulation of inflammatory responses to lung injury repair that culminates in fibrosis. This concept may be extended to the more proximal airways, as illustrated by the demonstration that conditional depletion of airway progenitor (Clara) cells in a transgenic mouse model induces peribronchiolar fibrosis (42).…”

Section: Pathobiological Updates In Pulmonary Fibrosis Infection and mentioning

confidence: 99%

Update in Diffuse Parenchymal Lung Disease 2011

Luckhardt¹,

Müller–Quernheim²,

Thannickal³

2012

Am J Respir Crit Care Med

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Conditional Depletion of Airway Progenitor Cells Induces Peribronchiolar Fibrosis

Cited by 71 publications

References 53 publications

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

Roles for β-Catenin and Doxycycline in the Regulation of Respiratory Epithelial Cell Frequency and Function

Update in Diffuse Parenchymal Lung Disease 2011

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