Ontogeny of Apoptosis during Lung Development

Kresch, Mitchell J.; Christian, Constance; Wu, Fengying; Hussain, Naveed

doi:10.1203/00006450-199803000-00020

Cited by 98 publications

(108 citation statements)

References 23 publications

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“…Consistent with the low apoptotic rate normally observed in postnatal lungs, 44 few positive cells were detected by terminal dUTP nick-end labeling (TUNEL) assay in the pulmonary tissue of both wild-type and Hoxa5 Ϫ/Ϫ specimens at all stages tested (not shown). Thus, apoptosis did not contribute significantly to the delayed lung growth.…”

Section: Consequences Of the Hoxa5 Mutation On Pulmonary Weight Prolmentioning

confidence: 52%

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

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The involvement of genes controlling embryonic processes in the etiology of diseases often escapes attention because of the focus given to their inherent developmental role. Hoxa5 belongs to the Hox gene family encoding transcription factors known for their role in skeletal patterning. Hoxa5 is required for embryonic respiratory tract morphogenesis. We now show that the loss of Hoxa5 function has severe repercussions on postnatal lung development. Hoxa5؊/؊ lungs present an emphysema-like morphology because of impaired alveogenesis. Chronic inflammation characteristics, including goblet cell hyperplasia, mucus hypersecretion, and recruitment of inflammatory cells, were also observed. Altered cell specification during lung morphogenesis triggered goblet cell anomalies. In addition, the defective motility of alveolar myofibroblast precursors in the embryonic lung led to the mispositioning of the alveolar myofibroblasts and to abnormal elastin deposition postnatally. Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5 ؊/؊ lungs. They constituted an attractive stimulus to recruit activated macrophages that in turn generated a positive feedback loop that perpetuated macrophage accumulation in the lung. The present work corroborates the notion that altered Hox gene expression may predispose to lung pathologies. Lung morphogenesis relies on finely orchestrated processes that initiate from the outpocketing and the elongation of the foregut endoderm into the surrounding mesenchyme. The lung bud then branches extensively giving rise to saccules that expend and subdivide to ultimately produce alveoli. In the mouse, the main stem bronchi form at approximately embryonic day (E) 9.5, and ramification organized by signaling centers shapes the respiratory tree during the pseudoglandular period that extends from E14.0 to E16.5. At late gestational stages, saccules are found at the end of each terminus of the pulmonary tree. The last step of lung morphogenesis occurs between postnatal day (P) 5 and P30, and it aims at multiplying the respiratory surface for vital gas exchanges after birth by modifying the distal lung architecture through the process of alveogenesis. During each step of lung development, the concerted action of transcriptional regulators, signaling molecules, their associated receptors and downstream effectors governs branching morphogenesis and lung maturation by integrating cellular proliferation, differentiation, apoptosis, and migration.

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Section: Consequences Of the Hoxa5 Mutation On Pulmonary Weight Prolmentioning

confidence: 52%

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

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“…In prototypical models of apoptotic cell death, as p113 decreases due to cleavage by caspase-3, p85 increases proportionately (2). Therefore, some of the p85 content we observed is consistent with previous observations that apoptosis is part of normal development in both fetal (20) and neonatal lung (31)(32)(33). We observed that in RFL p113 content decreased significantly in late gestation, but without a proportional increase in p85 ( Figures 1A and 1B).…”

Section: Discussionsupporting

confidence: 81%

“…For the entire period, Embryonic Day 16 to adulthood, the decrease in p113 was significant (n ϭ 28, R 2 ϭ 0.27, P Ͻ 0.005). The 85-kD fragment (p85) was also detected ( Figure 1A), consistent with observations that both fetal (20) and neonatal rat lung undergo apoptosis (31)(32)(33). However, the content of p85 did not increase proportionately to the decrease in p113 in late gestation ( Figure 1B); p85 content was relatively constant prenatally (n ϭ 16, R 2 ϭ 0.003) and decreased after birth through adulthood (n ϭ 16, R 2 ϭ 0.86, P Ͻ 0.001).…”

Section: Content Of Parp-1 Protein In Fetal and Postnatal Rat Lungsupporting

confidence: 73%

“…Subcellular fractionation showed that the cytoplasmic signal was due to p85 ( Figure 6). In addition, immunohistochemical studies showed that there was abundant cytoplasmic PARP-1 localization in cells not known to undergo apoptosis in developing lung (i.e., smooth muscle cells, Figures 3B and 4B) (9,24,30,32). As noted above, the cytoplasmic appearance of PARP-1 differs in different cell types, granular in epithelial cells and diffusely throughout the cytoplasm in smooth muscle cells.…”

Section: Discussionmentioning

confidence: 98%

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Developmental Implications

ICTs and Development

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Poly(ADP-ribose) polymerase 1 (PARP-1) is the predominant NADdependent modifying enzyme in DNA repair, transcription, and apoptosis; its involvement in development has not been defined. Here, we report expression and cellular localization of PARP-1 in developing rat and human fetal lung, in vivo and in explant culture, and effects of inhibiting PARP-1 activity on lung surfactant protein (SP) expression. PARP-1 was expressed as 113-kD (p113) and 85-kD (p85) fragment in both rat and human lung. In rat lung, p113 content by Western was maximal at Embryonic Days 16-18, decreased sharply by Embryonic Day 20, and continued to decrease postnatally. p85 level was constant in the fetus and decreased postnatally. In human fetal lung, both PARP-1 mRNA expression and protein content changed little between 15 and 24 wk. Immunohistochemistry for PARP-1 in Embryonic Day 18 rat lung showed predominantly nuclear staining in most cells. In later gestation and postnatally, PARP-1 staining was primarily cytoplasmic and progressively restricted to a subset of cells, mainly bronchial epithelial and smooth muscle cells. Cell subfractionation showed that p113 localized to nucleus and p85 to cytoplasm. Inhibition of PARP-1 activity by 5-iodo-6-amino-1,2-benzopyrone in fetal rat lung explant culture did not affect SP-A and -B mRNA, but significantly increased SP-C mRNA. These findings indicate that in lung (i ) PARP-1 is abundantly expressed during fetal development; (ii) p113 and p85 levels are differentially regulated; (iii) PARP-1 undergoes complex developmental changes in cellular and subcellular expression, including extensive cytoplasmic localization; and (iv) inhibition of PARP-1 activity differentially affects expression of SPs.Poly (ADP-ribose) polymerase-1 (PARP-1) is a 113-kD enzyme that catalyzes the covalent attachment of ADP-ribose units [poly (ADP-ribosyl)ation] to acceptor molecules, using NADϩ as a substrate. Studies over the last decade indicate that PARP-1 has a prominent role in the process of apoptosis (1). Because PARP-1 is a target of caspases, such as caspase 3, which are important for execution of the apoptotic pathway, evaluating PARP-1 cleavage products by Western analysis has been a useful way of confirming and following the process of apoptosis (2). Additionally, other studies have been aimed at defining the role PARP-1 plays in a broad range of biological processes important for the genomic integrity, differentiation, and functioning of nonapoptotic cells (3).The gene encoding PARP-1 is highly conserved and present in almost all eukaryotes, which is consistent with its playing an important role in fundamental biological events (4). Although the exact physiologic roles remain to be defined, PARP-1 and (Received in original form June 27, 2003 and in revised form December 19, 2003) poly (ADP-ribosyl)ation have been associated with a number of functions, including DNA repair (5) and replication (6, 7), cell cycle regulation (8), cell proliferation (9), differentiation (10-12), and cell death (13,14). The dro...

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“…We 10 -12 and others 13,14 have demonstrated that moderate and precisely timed alveolar epithelial type II cell apoptosis is an integral component of physiological postcanalicular lung remodeling in mice, rats, and rabbits. Although the exact biological role of apoptosis in alveologenesis remains uncertain, its choreographed occurrence across mammalian species strongly suggests apoptotic elimination of surplus type II cells during perinatal alveolar remodeling is a naturally occurring and developmentally relevant event.…”

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confidence: 99%

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

Paepe

Gundavarapu

Tantravahi

et al. 2008

The American Journal of Pathology

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Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasiaassociated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs. Transgenic (TetOp) 7 -FasL responder mice, generated by pronuclear microinjection, were bred with Clara cell secretory protein (CCSP)-rtTA activator mice. Doxycycline (Dox) was administered from embryonal day 14 to postnatal day 7, and lungs were studied between embryonal day 19 and postnatal day 21. Dox administration induced marked respiratory epithelium-specific FasL mRNA and protein up-regulation in double-transgenic CCSP-rtTA

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Ontogeny of Apoptosis during Lung Development

Cited by 98 publications

References 23 publications

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Developmental Implications

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

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