Toll‐like receptor signaling inhibits structural development of the distal fetal mouse lung

Prince, Lawrence S.; Dieperink, Heather I.; Okoh, Victor; Fierro-Perez, German Alejandro; Lallone, Roger L.

doi:10.1002/dvdy.20362

Cited by 64 publications

(73 citation statements)

References 31 publications

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“…3B). Addition of the NF-B inhibitor parthenolide (19) to the media slightly decreased baseline caspase 3 activity, and inhibited the increase in caspase 3 activity seen with exposure to 95% oxygen. Activation of NF-B with lipopolysaccharide also increased caspase 3 activity, but to a lesser degree compared with 95% oxygen.…”

Section: Resultsmentioning

confidence: 93%

Hyperoxia and Apoptosis in Developing Mouse Lung Mesenchyme

2006

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Hyperoxia contributes to the development of bronchopulmonary dysplasia in former premature infants. Injurious environmental factors such as hyperoxia may disrupt distal airway branching and alveolar septation, as these critical stages in lung development occur following birth in extremely premature infants. To test if hyperoxia directly inhibited distal airway branching, we cultured E16 fetal mouse lung explants in either 20% (control) or 95% oxygen (hyperoxia). Hyperoxia reduced the number of distal airways to less than 50% of controls. Explants cultured in 95% oxygen also had fewer complex distal airways compared with controls. Mesenchymal cells adjacent to distal airways in hyperoxic explants appeared apoptotic by phase microscopy. Consistent with increased apoptosis, explants cultured in hyperoxia had increased caspase 3/7 activity compared with controls. Hyperoxia also increased mesenchymal caspase 3 expression and annexin V binding within cultured explants as visualized by fluorescence microscopy. We measured increased annexin V binding in isolated primary fetal lung mesenchymal cells cultured in 95% oxygen suggesting a direct effect on cells within the mesenchyme. Hyperoxia can lead to NF-B activation, which mediates inflammatory cascades and may protect cells from apoptosis. We detected NF-B activation and nuclear p65 localization in explants exposed to 48 h of hyperoxia. Inhibition of NF-B prevented the hyperoxia-induced activation of caspase 3. NF-B activation may therefore contribute to apoptosis in the developing fetal mouse lung following hyperoxia exposure. Our data suggest hyperoxia inhibits distal airway branching and directly induces apoptosis of the fetal mouse lung mesenchyme. (Pediatr Res 59: [185][186][187][188][189][190] 2006) B ranching of distal airway saccules into immature alveoli begins in the canalicular phase of human fetal lung development at 20 -22 wk gestation, equivalent to embryonal day 16 (E16) in mice (1-4). As the fetal lung progresses from the canalicular to alveolar phase of development (30 wk gestation in humans, E18 in mice), mesenchymal cells adjacent airways undergo apoptosis, allowing formation of thin interstitial septae (5). Alveoli then continue to divide and septate following birth. Extremely premature infants delivered between 23-27 wk are therefore born before distal lung branching is complete and before alveolarization begins. Abnormal distal airway branching and dysregulated mesenchymal apoptosis in these premature infants may contribute to the pathogenesis of bronchopulmonary dysplasia(6).The lungs of infants with bronchopulmonary dysplasia contain large, simplified alveolar structures (6). With this pathology, the surface area for gas exchange is reduced and the lungs are prone to heterogeneous patterns of atelectasis and hyperinflation. Both arrested lung development and lung injury contribute to the pathogenesis of bronchopulmonary dysplasia (7). In addition to contributing to lung injury, hyperoxia inhibits normal alveolar development in roden...

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Section: Resultsmentioning

confidence: 93%

Hyperoxia and Apoptosis in Developing Mouse Lung Mesenchyme

2006

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“…Disrupting fibronectin association using function-blocking antibodies reduces branching of embryonic lung explants, whereas exogenous addition of fibronectin enhances branching (De Langhe et al, 2005;Sakai et al, 2003). Consistently, treatments that cause mislocalization of fibronectin fibrils block airway branching (Prince et al, 2005). Fibronectin is also implicated in branching morphogenesis in the developing kidney, where fibronectin expression is enhanced in the metanephric mesenchyme adjacent to the branching ureteric bud, and induces branching tubulogenesis of kidney epithelial cells (Santos and Nigam, 1993) and embryonic ureteric bud cells (Ye et al, 2004) in culture.…”

Section: Matrix-driven Branchingmentioning

confidence: 80%

Cellular and physical mechanisms of branching morphogenesis

2014

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Branching morphogenesis is the developmental program that builds the ramified epithelial trees of various organs, including the airways of the lung, the collecting ducts of the kidney, and the ducts of the mammary and salivary glands. Even though the final geometries of epithelial trees are distinct, the molecular signaling pathways that control branching morphogenesis appear to be conserved across organs and species. However, despite this molecular homology, recent advances in cell lineage analysis and real-time imaging have uncovered surprising differences in the mechanisms that build these diverse tissues. Here, we review these studies and discuss the cellular and physical mechanisms that can contribute to branching morphogenesis.

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“…While TLR4 studies provide an interesting window into RSV pathogenesis, other genes and risk factors have also been noted to influence disease severity (6-8, 10, 53). In fact, GATA3/T-bet ratios and Th2 bias may be part of a downstream pathogenic pathway modified at various levels by different genes affecting pulmonary function (54,55) and/or immune responses (8)(9)(10)34) in the context of the environment and its epigenetic modifications.…”

Section: Discussionmentioning

confidence: 99%