Lung structure phenotype variation in inbred mouse strains revealed through in vivo micro-CT imaging

Thiesse, Jacqueline; Namati, Eman; Sieren, Jessica C.; Smith, Amanda R.; Reinhardt, Joseph M.; Hoffman, Eric A.; McLennan, Geoffrey

doi:10.1152/japplphysiol.01322.2009

Cited by 81 publications

(94 citation statements)

References 28 publications

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“…Lung specimens were scanned at an isotropic resolution of 10 microns at 45 kVp, 200 mAs (81). CT image raw data were analyzed using AMIRA software (FEI) to create volume renderings (82). 3D segmentation to compartmentalize the lung into tissue and conducting airway was performed based on threshold of gray value difference between tissue and air.…”

Section: Cldn18mentioning

confidence: 99%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

126

116

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Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

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Section: Cldn18mentioning

confidence: 99%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

126

116

View full text Add to dashboard Cite

show abstract

“…Elegant studies have compared and contrasted in vivo and ex vivo micro-CT scanning of normal murine lungs [11] or highlighted differences in lung structure between mouse strains [20]. Few studies, however, have addressed the use of micro-CT for evaluation of the degree of fibrotic change in murine models of lung fibrosis.…”

Section: Interstitial Lung Diseases | Cj Scotton Et Almentioning

confidence: 99%

Ex vivomicro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation

et al. 2013

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Research into the pathogenesis underlying the development of idiopathic pulmonary fibrosis is hampered by a repertoire of animal models that fail to recapitulate all the features of the human disease. Better use and understanding of what the animal models represent may improve clinical predictability. We interrogated ex vivo micro-computed tomography (CT) as a novel end-point measure in the mouse model of bleomycin-induced lung fibrosis (BILF), and to evaluate a therapeutic dosing regimen for preclinical drug evaluation.A detailed characterisation of BILF was performed using standard end-point measures (lung hydroxyproline and histology). High resolution micro-CT (,13.7 mm voxel size) was evaluated for quantifying the extent and severity of lung fibrosis.The period from 14 to 28 days following bleomycin instillation represents progression of established fibrosis. A therapeutic dosing regimen during this period was validated using a transforming growth factor-b receptor-1 kinase inhibitor, and micro-CT provided a highly sensitive and quantitative measure of fibrosis. Moreover, fibrotic lesions did not completely resolve, but instead persisted for o6 months following a single insult with bleomycin.Ex vivo micro-CT analysis of BILF allows robust evaluation of therapeutic dosing once fibrosis is already well established, requiring fewer mice than conventional biochemical end-points. @ERSpublications Micro-CT has improved out understanding of the bleomycin model of fibrotic lung disease for preclinical drug evaluation

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“…By casting and acquiring high-contrast data, CT/MRI image processing similar to our custom software could semiautomatically identify the large airways (to the sixth generation). Subsequent studies of living mice did not label the airways and thus had to perform extensive manual analysis, including tracing airways slice-by-slice across 700 slices and manually quantifying diameters, length, and branch angles (10). The casting method in the current study, based on binding of labeled streptavidin to endogenous biotin in the airway epithelium, can be used with tissue clearing, whole organ laserscanning microscopy, and colabeling other epitopes.…”

Section: Identifying 3d Tissue Compartments and Airway Morphometrymentioning

confidence: 99%

“…Although lung nerves initially travel in conspicuous bundles, visualizing their individual processes at effector/receptor sites requires micron-scale optical resolution and a labeling method to increase signal contrast and visibility. This is not possible with current whole lung imaging approaches (e.g., micro-computed tomography and magnetic resonance imaging [MRI]) (9,10). Whole lung imaging in animal models has a more limited range of labeling available and typically millimeter resolution with a higher resolution possible when examining a small portion of the lung (11)(12)(13).…”

mentioning

confidence: 99%

Tissue Optical Clearing, Three-Dimensional Imaging, and Computer Morphometry in Whole Mouse Lungs and Human Airways

Scott

Blum

Fryer

et al. 2014

Am J Respir Cell Mol Biol

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In whole adult mouse lung, full identification of airway nerves (or other cellular/subcellular objects) has not been possible due to patchy distribution and micron-scale size. Here we describe a method using tissue clearing to acquire the first complete image of threedimensional (3D) innervation in the lung. We then created a method to pair analysis of nerve (or any other colabeled epitope) images with identification of 3D tissue compartments and airway morphometry by using fluorescent casting and morphometry software (which we designed and are making available as open-source). We then tested our method to quantify a sparse heterogeneous nerve population by examining visceral pleural nerves. Finally, we demonstrate the utility of our method in human tissue to image full thickness innervation in irregular 3D tissue compartments and to quantify sparse objects (intrinsic airway ganglia). Overall, this method can uniquely pair the advantages of whole tissue imaging and cellular/subcellular fluorescence microscopy.

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Lung structure phenotype variation in inbred mouse strains revealed through in vivo micro-CT imaging

Abstract: Thiesse J, Namati E, Sieren JC, Smith AR, Reinhardt JM, Hoffman EA, McLennan G. Lung structure phenotype variation in inbred mouse strains revealed through in vivo micro-CT imaging. J Appl Physiol

Cited by 81 publications

References 28 publications

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Ex vivomicro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation

Tissue Optical Clearing, Three-Dimensional Imaging, and Computer Morphometry in Whole Mouse Lungs and Human Airways

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