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David Warburton - One of the best experts on this subject based on the ideXlab platform.
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Retraction: Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic Lung Epithelium. Development doi: 10.1242/dev.058479.
Development (Cambridge England), 2017Co-Authors: Ahmed H.k. El-hashash, Gianluca Turcatel, Denise Al Alam, Sue Buckley, Hiroshi Tokumitsu, Saverio Bellusci, David WarburtonAbstract:The journal is retracting ‘Eya1 controls cell polarity, spindle orientation, cell fate and Notch signalling in distal embryonic Lung Epithelium’ by Ahmed HK El-Hashash, Gianluca Turcatel, Denise Al Alam, Sue Buckley, Hiroshi Tokumitsu, Saverio Bellusci and David Warburton (2011). [Development
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eya1 protein phosphatase regulates tight junction formation in Lung distal Epithelium
Journal of Cell Science, 2012Co-Authors: Gianluca Turcatel, Denise Al Alam, David Warburton, Ahmed H K Elhashash, Saaket Varma, Mohamed BerikaAbstract:Little is known about the regulatory mechanisms underlying Lung epithelial tight junction (TJ) assembly, which is inextricably linked to the preservation of epithelial polarity, and is highly coordinated by proteins that regulate epithelial cell polarity, such as aPKCζ. We recently reported that Eya1 phosphatase functions through aPKCζ–Notch1 signaling to control cell polarity in the Lung Epithelium. Here, we have extended these observations to TJ formation to demonstrate that Eya1 is crucial for the maintenance of TJ protein assembly in the Lung Epithelium, probably by controlling aPKCζ phosphorylation levels, aPKCζ-mediated TJ protein phosphorylation and Notch1–Cdc42 activity. Thus, TJs are disassembled after interfering with Eya1 function in vivo or during calcium-induced TJ assembly in vitro. These effects are reversed by reintroduction of wild-type Eya1 or partially inhibiting aPKCζ in Eya1siRNA cells. Moreover, genetic activation of Notch1 rescues Eya1−/− Lung epithelial TJ defects. These findings uncover novel functions for the Eya1–aPKCζ–Notch1–Cdc42 pathway as a crucial regulatory mechanism of TJ assembly and polarity of the Lung Epithelium, providing a conceptual framework for future mechanistic and translational studies in this area.
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Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic Lung Epithelium
Development (Cambridge England), 2011Co-Authors: Ahmed H.k. El-hashash, Gianluca Turcatel, Denise Al Alam, Sue Buckley, Hiroshi Tokumitsu, Saverio Bellusci, David WarburtonAbstract:Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic Lung distal Epithelium. Herein, we provide the first evidence that embryonic Lung distal Epithelium is polarized with characteristic perpendicular cell divisions. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic Lung distal Epithelium. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal Lung Epithelium, probably by controlling aPKCζ phosphorylation. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. In addition, in Eya1−/− Lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1−/− Lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. Indeed, genetic activation of Notch partially rescues Eya1−/− Lung epithelial defects. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic Lung Epithelium.
Bettina Löffler - One of the best experts on this subject based on the ideXlab platform.
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combined action of influenza virus and staphylococcus aureus panton valentine leukocidin provokes severe Lung Epithelium damage
The Journal of Infectious Diseases, 2012Co-Authors: Silke Niemann, Christina Ehrhardt, Eva Medina, Kathrin Warnking, Lorena Tuchscherr, Vanessa Heitmann, Stephan Ludwig, Georg Peters, Bettina LöfflerAbstract:Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton–Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the Lung Epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway Epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.
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Combined Action of Influenza Virus and Staphylococcus aureus Panton–Valentine Leukocidin Provokes Severe Lung Epithelium Damage
The Journal of infectious diseases, 2012Co-Authors: Silke Niemann, Christina Ehrhardt, Eva Medina, Kathrin Warnking, Lorena Tuchscherr, Vanessa Heitmann, Stephan Ludwig, Georg Peters, Bettina LöfflerAbstract:Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton–Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the Lung Epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway Epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.
Silke Niemann - One of the best experts on this subject based on the ideXlab platform.
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combined action of influenza virus and staphylococcus aureus panton valentine leukocidin provokes severe Lung Epithelium damage
The Journal of Infectious Diseases, 2012Co-Authors: Silke Niemann, Christina Ehrhardt, Eva Medina, Kathrin Warnking, Lorena Tuchscherr, Vanessa Heitmann, Stephan Ludwig, Georg Peters, Bettina LöfflerAbstract:Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton–Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the Lung Epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway Epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.
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Combined Action of Influenza Virus and Staphylococcus aureus Panton–Valentine Leukocidin Provokes Severe Lung Epithelium Damage
The Journal of infectious diseases, 2012Co-Authors: Silke Niemann, Christina Ehrhardt, Eva Medina, Kathrin Warnking, Lorena Tuchscherr, Vanessa Heitmann, Stephan Ludwig, Georg Peters, Bettina LöfflerAbstract:Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton–Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the Lung Epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway Epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches.
Edward E. Morrisey - One of the best experts on this subject based on the ideXlab platform.
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wnt β catenin signaling accelerates mouse Lung tumorigenesis by imposing an embryonic distal progenitor phenotype on Lung Epithelium
Journal of Clinical Investigation, 2011Co-Authors: Eugenia C Pachecopinedo, Amy C. Durham, Kathleen M. Stewart, Ashley M. Goss, Francesco J. Demayo, Edward E. MorriseyAbstract:Although mutations in Kras are present in 21% of Lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with Lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in Lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar Epithelium of the adult mouse Lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar Epithelium to the highly proliferative distal progenitors found in the embryonic Lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in Lung Epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.
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Wnt/β-catenin signaling accelerates mouse Lung tumorigenesis by imposing an embryonic distal progenitor phenotype on Lung Epithelium
The Journal of clinical investigation, 2011Co-Authors: Eugenia C. Pacheco-pinedo, Amy C. Durham, Kathleen M. Stewart, Ashley M. Goss, Francesco J. Demayo, Edward E. MorriseyAbstract:Although mutations in Kras are present in 21% of Lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with Lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in Lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar Epithelium of the adult mouse Lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar Epithelium to the highly proliferative distal progenitors found in the embryonic Lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in Lung Epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.
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The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in Lung Epithelium.
The Journal of biological chemistry, 2002Co-Authors: Joel Weidenfeld, Lili Zhang, Weiguo Shu, Sarah E. Millar, Edward E. MorriseyAbstract:In this study, we find that WNT7b is the only member of the WNT family of autocrine/paracrine signaling molecules whose expression in the Lung is restricted to the airway Epithelium during embryonic development. To study the transcriptional mechanisms that underlie this restricted pattern of WNT7b expression, we isolated the proximal 1.0-kb mouse WNT7b promoter and mapped the transcriptional start sites. Transfection of the Lung epithelial cell line MLE-15, which expresses WNT7b, shows that the 1.0-kb mouse WNT7b promoter is highly active in Lung epithelial cells. This region of the WNT7b promoter contains several DNA binding sites for the important Lung-restricted transcription factors TTF-1, GATA6, and Foxa2. Electrophoretic mobility shift assays showed that TTF-1, GATA6, and Foxa2 can bind to a specific subset of their consensus DNA binding sites within the WNT7b promoter. Using cotransfection assays, we demonstrate that TTF-1, GATA6, and Foxa2 can trans-activate the WNT7b promoter in NIH-3T3 cells. Truncation of GATA6 or Foxa2 binding sites reduced the ability of these transcriptional regulators to trans-activate the WNT7b promoter. Finally, the minimal 118-bp region of the mouse WNT7b promoter containing only TTF-1 binding sites was synergistically activated by TTF-1 and GATA6, and we show that TTF-1 and GATA6 physically interact in vivo. Together, these results suggest that WNT7b gene expression in the Lung Epithelium is regulated in a combinatorial fashion by TTF-1, GATA6, and Foxa2.
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GATA6 regulates differentiation of distal Lung Epithelium.
Development (Cambridge England), 2002Co-Authors: Honghua Yang, Lili Zhang, Jeffrey A. Whitsett, Edward E. MorriseyAbstract:GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal Epithelium of the Lung during development. To define the role that GATA6 plays during Lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal Lung Epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway Epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.
Norbert Suttorp - One of the best experts on this subject based on the ideXlab platform.
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Lung Epithelium as a sentinel and effector system in pneumonia molecular mechanisms of pathogen recognition and signal transduction
Respiratory Research, 2006Co-Authors: Stefan Hippenstiel, Bernd Schmeck, Bastian Opitz, Norbert SuttorpAbstract:Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and Lung Epithelium comprises a large surface between host and environment and is attacked as a primary target during Lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the Lung Epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the Epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of Lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of Lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics.
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Lung Epithelium as a sentinel and effector system in pneumonia – molecular mechanisms of pathogen recognition and signal transduction
Respiratory research, 2006Co-Authors: Stefan Hippenstiel, Bernd Schmeck, Bastian Opitz, Norbert SuttorpAbstract:Pneumonia, a common disease caused by a great diversity of infectious agents is responsible for enormous morbidity and mortality worldwide. The bronchial and Lung Epithelium comprises a large surface between host and environment and is attacked as a primary target during Lung infection. Besides acting as a mechanical barrier, recent evidence suggests that the Lung Epithelium functions as an important sentinel system against pathogens. Equipped with transmembranous and cytosolic pathogen-sensing pattern recognition receptors the Epithelium detects invading pathogens. A complex signalling results in epithelial cell activation, which essentially participates in initiation and orchestration of the subsequent innate and adaptive immune response. In this review we summarize recent progress in research focussing on molecular mechanisms of pathogen detection, host cell signal transduction, and subsequent activation of Lung epithelial cells by pathogens and their virulence factors and point to open questions. The analysis of Lung epithelial function in the host response in pneumonia may pave the way to the development of innovative highly needed therapeutics in pneumonia in addition to antibiotics.
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Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium
Infection and Immunity, 2004Co-Authors: Bernd Schmeck, Phillipe Dje N'guessan, Timothy J. Mitchell, Simone Rosseau, Andreas C Hocke, Norbert Suttorp, Ralph Gross, Sven Hammerschmidt, Stefan HippenstielAbstract:Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung Epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with Lung epithelial cells. Apoptosis of Lung Epithelium is involved in some bacterial Lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H2O2. Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin- and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.
