Type I cell-like morphology in tight alveolar epithelial monolayers

Cheek, Jeffrey M.; Evans, Michael J.; Crandall, Edward D.

doi:10.1016/0014-4827(89)90337-6

Cited by 126 publications

(92 citation statements)

References 31 publications

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“…AT2 cells are believed to serve as the progenitors for repair of the alveolar epithelium after injury, being capable of both self-renewal and of giving rise to AT1 cells through a process of transdifferentiation (37). Similar to observations in vivo, AT2 cells in primary culture lose their phenotypic hallmarks and gradually acquire the morphologic features of AT1 cells (38). The cells increasingly express all available AT1 cell phenotypic markers, suggesting that AT2 cells in vitro transdifferentiate toward an AT1 cell phenotype (AT1-like cells) (15,39).…”

Section: Emt In Lungsupporting

confidence: 68%

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Willis

duBois²,

Borok³

2006

Proceedings of the American Thoracic Society

447

348

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An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow-derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial-mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell-cell attachment, polarity and epithelialspecific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-␤1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.

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Section: Emt In Lungsupporting

confidence: 68%

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Willis

duBois²,

Borok³

2006

Proceedings of the American Thoracic Society

447

348

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“…Distal airspaces of the lung are lined with a continuous epithelium comprised of alveolar epithelial type I (AT1) and type II (AT2) cells. It is generally accepted that primary cultured rat AT2 cells transdifferentiate into an AT1 cell-like phenotype (25,26). Primary cultured rat AEC monolayers (RAECMs) derived from freshly isolated AT2 cells exhibit high transepithelial electrical resistance (R T .…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

Alveolar Epithelial Cell Injury Due to Zinc Oxide Nanoparticle Exposure

Kim¹,

Fazlollahi²,

Kennedy³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Although inhalation of zinc oxide (ZnO) nanoparticles (NPs) is known to cause systemic disease (i.e., metal fume fever), little is known about mechanisms underlying injury to alveolar epithelium. Objectives: Investigate ZnO NP-induced injury to alveolar epithelium by exposing primary cultured rat alveolar epithelial cell monolayers (RAECMs) to ZnO NPs. Methods: RAECMs were exposed apically to ZnO NPs or, in some experiments, to culture fluid containing ZnCl 2 or free Zn released from ZnO NPs. Transepithelial electrical resistance (R T ) and equivalent short-circuit current (I EQ ) were assessed as functions of concentration and time. Morphologic changes, lactate dehydrogenase release, cell membrane integrity, intracellular reactive oxygen species (ROS), and mitochondrial activity were measured. Measurements and Main Results: Apical exposure to 176 mg/ml ZnO NPs decreased R T and I EQ of RAECMs by 100% over 24 hours, whereas exposure to 11 mg/ml ZnO NPs had little effect. Changes in R T and I EQ caused by 176 mg/ml ZnO NPs were irreversible. ZnO NP effects on R T yielded half-maximal concentrations of approximately 20 mg/ml. Apical exposure for 24 hours to 176 mg/ml ZnO NPs induced decreases in mitochondrial activity and increases in lactate dehydrogenase release, permeability to fluorescein sulfonic acid, increased intracellular ROS, and translocation of ZnO NPs from apical to basolateral fluid (most likely across injured cells and/or damaged paracellular pathways). Conclusions: ZnO NPs cause severe injury to RAECMs in a dose-and time-dependent manner, mediated, at least in part, by free Zn released from ZnO NPs, mitochondrial dysfunction, and increased intracellular ROS.Keywords: epithelial monolayers; zinc toxicity; reactive oxygen species; mitochondrial damage; plasma membrane integrity Nanoparticles (NPs) are used in many commercial products and new applications in biomedicine, yet their fate, potential toxicity, and mechanisms of translocation in biological cells, tissues, and organs (including the lung) have not been well defined. Some, but not all, inhaled NPs (including ambient ultrafine particulates that overlap in size with NPs) have been reported to be associated with adverse health effects (1, 2). There is evidence that measurable amounts of these inhaled NPs are found in end organs (e.g., liver, spleen, and heart) after inhalation (3-6), possibly leading to thrombosis, atherogenesis, and cardiac dysrhythmias (3,7,8). NPs found in end organs after inhalation are most likely to enter the systemic circulation across the epithelia of the lung, especially the alveolar epithelium, which constitutes a very thin biological barrier (z0.5 mm) and affords greater than 95% of the surface area (z100 m 2 in humans) in distal airspaces of the lung.Of the NPs and ambient ultrafine particulates studied to date, several metal (e.g., Fe, Zn, V, and Ni) and metal oxide (Fe 2 O 3, ZnO, V 2 O 5 , and NiO) NPs have the potential to cause inflammation and injury in lungs (9-12). Among metal and metal oxide NPs i...

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“…In this study, we report the microanatomical immunolocalization of MDR1/ mdr1 P-gp expression to alveolar epithelium within intact normal human and rat lung tissue, with clear localization evident on the luminal membranes of AE type I epithelium. Using a well characterized in vitro approach to study AE differentiation, namely, a rat primary culture model of AE cells (Dobbs et al, 1988;Cheek et al, 1989;Danto et al, 1992;Campbell et al, 1999), we went on to show the increased expression (confirmed by RT-PCR, Western blot, and immunoflow cytometry techniques) of mdr1/P-gp in these primary cultures as the AE culture model progressed toward an AE type I phenotype; freshly isolated rat AE type II cells seemed negative for mdr1/P-gp The functionality of P-gp within the AE primary cultures was established by a flow cytometric accumulation-retention assay using rhodamine-123 as substrate, and also by the polarized transport of vinblastine across confluent AE monolayers grown on semipermeable supports.…”

mentioning

confidence: 99%

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

Campbell¹,

Abulrob²,

Kandalaft³

et al. 2003

J Pharmacol Exp Ther

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The multidrug resistant (MDR) transporter P-glycoprotein (Pgp) is constitutively expressed in normal tissues, where its spatial distribution defines it as an important element reducing the systemic exposure and tissue access of potentially harmful xenobiotics. We sought to determine whether P-gp is functionally expressed within alveolar epithelium of lung, in particular within the predominant cell type of this barrier, the alveolar epithelial (AE) type I cell. By immunohistochemistry, MDR-1/ mdr-1 P-gp was localized to luminal membranes of AE type I epithelium within normal human and rat lung tissue. Using a primary rat cell culture model affording study of AE type II to AE type I differentiation, we observed increased expression (reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunoflow cytometry techniques) of mdr-1a and mdr-1b P-gp in the cultures as they adopted an AE type I phenotype; freshly isolated AE type II cells were negative for mdr-1/P-gp. The functionality of P-gp within the AE cultures was demonstrated by a flow cytometric accumulation-retention assay using rhodamine-123 as substrate, and also by the polarized transport of vinblastine across confluent AE type I monolayers (basal-to-apical permeability was 3-fold that of apical-to-basal permeability), which was found to be comparable with the P-gp transport barrier presented by Caco-2 cell monolayers. The implications of localizing P-gp within alveolar epithelium is of significance to studies of fundamental respiratory cell biology as well as to further clarifying the nature of the barrier to xenobiotic transfer from alveolar airspace to pulmonary interstitium and capillary blood.P-Glycoprotein (P-gp) is a member of the ATP-binding cassette superfamily of membrane transport proteins that mediates the vectorial movement across cell membranes of a wide range of physicochemically diverse solutes (Stouch and Gudmundsson, 2002). In humans, two P-gp-related genes have been cloned and subsequently termed MDR1 and MDR3 (for review, see Ambudkar et al., 1999). The MDR1/P-gp gene product is recognized in particular to actively efflux from a cell a diverse range of cytotoxic drugs, a characteristic that is an important facet in the multidrug resistant (MDR) cell phenotype. Current evidence suggests that the MDR3/P-gp gene product does not contribute to an MDR phenotype.In rodents, three P-gp-related genes have been identified and designated mdr-1a, mdr-1b, and mdr-

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Type I cell-like morphology in tight alveolar epithelial monolayers

Cited by 126 publications

References 31 publications

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Alveolar Epithelial Cell Injury Due to Zinc Oxide Nanoparticle Exposure

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

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