Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Paepe, Monique E. De; Gundavarapu, Sravanthi; Tantravahi, Umadevi; Pepperell, John R.; Haley, Sheila A.; Luks, François I.; Mao, Quanfu

doi:10.2353/ajpath.2008.071123

Cited by 31 publications

(55 citation statements)

References 76 publications

(89 reference statements)

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“…[2][3][4] In addition, several reports [5][6][7] have shown that the lungs of ventilated preterm infants with early BPD show markedly increased levels of alveolar epithelial cell death. Recently, it was demonstrated that increased alveolar epithelial apoptosis induced by Fas ligand (FasL) overexpression in newborn mice is sufficient to disrupt alveolar remodeling, 8 supporting the notion that the loss of alveolar epithelial cells plays a critical role in the arrested alveolar development seen in BPD. These findings suggest that cell-based therapy aimed at restoring or protecting the alveolar epithelium in injured newborn lungs may be beneficial.…”

mentioning

confidence: 89%

“…The previously described lung-specific FasL-overexpressing transgenic mouse 8,51 was used as a model for neonatal lung injury/BPD. This model is based on a tetracycline-dependent tetracycline-inducible overexpression system to achieve time-specific FasL-transgene expression in the respiratory epithelium.…”

Section: Animal Husbandry and Tissue Processingmentioning

confidence: 99%

“…This model is based on a tetracycline-dependent tetracycline-inducible overexpression system to achieve time-specific FasL-transgene expression in the respiratory epithelium. 8 Transgenic (tetOp) 7 -FasL mice ("responder line") were crossed with Clara cell secretory protein (CCSP)-rtTA mice ("activator line") (provided by Dr J. Whitsett, University of Cincinnati, Cincinnati, OH) 54 8 The transgenic animals are generated in an FVB/N genetic background and have an intact immune system.…”

Section: Animal Husbandry and Tissue Processingmentioning

confidence: 99%

“…8,51 When FasL overexpression is targeted to the perinatal period, this apoptosis-induced transgenic mouse model provides a faithful replication of both the early apoptotic injury and the subsequent alveolar simplification typical of preterm infants with BPD.…”

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confidence: 99%

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Alveolar Epithelial Cell Therapy with Human Cord Blood–Derived Hematopoietic Progenitor Cells

Paepe

Mao

Ghanta

et al. 2011

The American Journal of Pathology

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The role of umbilical cord blood (CB)-derived stem cell therapy in neonatal lung injury remains undetermined. We investigated the capacity of human CB-derived CD34؉ hematopoietic progenitor cells to regenerate injured alveolar epithelium in newborn mice. Doubletransgenic mice with doxycycline (Dox)-dependent lung-specific Fas ligand (FasL) overexpression, treated with Dox between embryonal day 15 and postnatal day 3, served as a model of neonatal lung injury. Singletransgenic non-Dox-responsive littermates were controls. CD34؉ cells (1 ؋ 10 5 to 5 ؋ 10 5 ) were administered at postnatal day 5 by intranasal inoculation. Engraftment, respiratory epithelial differentiation, proliferation, and cell fusion were studied at 8 weeks after inoculation. Engrafted cells were readily detected in all recipients and showed a higher incidence of surfactant immunoreactivity and proliferative activity in FasL-overexpressing animals compared with non-FasL-injured littermates. Cord blood-derived cells surrounding surfactant-immunoreactive type II-like cells frequently showed a transitional phenotype between type II and type I cells and/or type I cell-specific podoplanin immunoreactivity. Lack of nuclear colocalization of human and murine genomic material suggested the absence of fusion. In conclusion, human CB-derived CD34؉ cells are capable of longterm pulmonary engraftment, replication, clonal expansion, and reconstitution of injured respiratory epithelium by fusion-independent mechanisms. Cord blood-derived surfactant-positive epithelial cells appear to act as progenitors of the distal respiratory unit, analogous to resident type II cells. Graft proliferation and alveolar epithelial differentiation are promoted by lung injury.

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confidence: 89%

Section: Animal Husbandry and Tissue Processingmentioning

confidence: 99%

Section: Animal Husbandry and Tissue Processingmentioning

confidence: 99%

mentioning

confidence: 99%

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Alveolar Epithelial Cell Therapy with Human Cord Blood–Derived Hematopoietic Progenitor Cells

Paepe

Mao

Ghanta

et al. 2011

The American Journal of Pathology

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“…We have previously demonstrated that engagement of the Fas receptor in newborn lungs, either by activating anti-Fas antibody (35) or respiratory epithelium-specific FasL overexpression (63), results in increased alveolar epithelial apoptosis and disrupted alveolar remodeling. The present study implicates the Fas/FasL system as regulator of proliferation in hyperoxic lungs.…”

Section: Discussionmentioning

confidence: 99%

The Fas System Confers Protection against Alveolar Disruption in Hyperoxia-Exposed Newborn Mice

Mao

Gundavarapu²,

Patel³

et al. 2008

Am J Respir Cell Mol Biol

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The functional significance of the Fas/Fas-ligand (FasL) system in hyperoxia-induced lung injury and alveolar disruption in newborn lungs in vivo remains undetermined. To assess the role of the Fas/FasL system, we compared the effects of hyperoxia (95% O 2 from birth to Postnatal Day [P]7) in Fas-deficient lpr mice and wild-type mice. Alveolar disruption was more severe in hyperoxic lpr mice than in wildtype mice. In addition, a transient alveolarization defect was noted in normoxic lpr mice. Hyperoxia induced marked up-regulation of pulmonary Fas expression in wild-type mice, as well as elevated mRNA levels of pro-apoptotic Bax, Bad, and Bak. Pulmonary apoptotic activity was similar in hyperoxic wild-type and lpr mice. In contrast, lung growth and proliferation, assessed by stereologic volumetry and Ki67 proliferation studies, were significantly higher in hyperoxic wildtype mice compared with lpr mice, suggesting the Fas/FasL system has a pro-proliferative role in hyperoxic conditions. Levels of the prosurvival MAPkinase, pERK1/2, were significantly higher in hyperoxic wild-type mice compared with lpr mice, while pAkt levels were similar. These data suggest that the primary role of the Fas/FasL system in hyperoxic newborn lungs is pro-proliferative, rather than pro-apoptotic, and likely mediated through a Fas-ERK1/2 pathway. Fas-induced proliferation and lung growth in hyperoxic newborn lungs may counteract, in part, the detrimental effects of apoptosis mediated by non-Fas pathways, such as pro-apoptotic Bax/Bcl-2 family members. The capacity of the Fas/FasL signaling pathway to mediate protective rather than destructive functions in hyperoxic newborn lungs highlights the versatility of this complex pathway.

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Autophagy inducers restore impaired autophagy, reduce apoptosis, and attenuate blunted alveolarization in hyperoxia‐exposed newborn rats

Zhang

et al. 2018

Pediatric Pulmonology

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Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Cited by 31 publications

References 76 publications

Alveolar Epithelial Cell Therapy with Human Cord Blood–Derived Hematopoietic Progenitor Cells

Alveolar Epithelial Cell Therapy with Human Cord Blood–Derived Hematopoietic Progenitor Cells

The Fas System Confers Protection against Alveolar Disruption in Hyperoxia-Exposed Newborn Mice

Autophagy inducers restore impaired autophagy, reduce apoptosis, and attenuate blunted alveolarization in hyperoxia‐exposed newborn rats

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