Key developmental regulators change during hyperoxia‐induced injury and recovery in adult mouse lung

Pogach, Melanie; Cao, Yuxia; Millien, Guetchyn; Ramirez, María I.; Williams, Mary C.

doi:10.1002/jcb.21142

Cited by 43 publications

(39 citation statements)

References 59 publications

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“…Thyroid transcription factor 1 (TTF1), a key transcription factor in type II cell development, did not increase in hyperoxia (Fig. 4A), consistent with a previous report (14). Furthermore, C/EBP␣ siRNA injection did not change TTF1 mRNA levels in hyperoxia.…”

Section: Intrapulmonary Delivery Of C/ebp␣ Sirna Decreases C/ebp␣ Prosupporting

confidence: 90%

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

Guang

Hinson

Bordner

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-␣ (C/EBP␣) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBP␣ expression was significantly enhanced in the lungs of newborn mice. The increased C/EBP␣ protein was predominantly located in alveolar type II cells. Silencing of C/EBP␣ with a transpulmonary injection of C/EBP␣ small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBP␣ hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNAinjected mice. These data suggest that C/EBP␣ is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair.CCAAT/enhancer binding protein-␣; developing lung injury; small interfering RNA; recovery POSTNATAL LUNG DEVELOPMENT involves a series of coordinated events, including active cell proliferation and differentiation, to promote proper alveolar formation. Parenchymal lung cells, fibroblasts, endothelial cells, and epithelial type II cells have distinct growth patterns and specific proliferation rates, beginning in the neonatal period (9). Imbalance of growth factors, inflammatory insults, and oxidative stress (reviewed in Ref. 16) could alter these processes, resulting in impaired lung development. Hyperoxic exposure is well known for disrupting alveolarization in the developing lung, because it inhibits the growth of epithelial, fibroblast, and endothelial cells forming the alveoli (5,19). Several studies have demonstrated that hyperoxia results in alveolar growth arrest, induction of cell cycle inhibitory proteins (13), altered surfactant protein (SP) production (reviewed in Ref. 4), and disrupted extracellular matrix signaling (1). The effect of hyperoxia on the proliferation of specific lung cell types is not well defined.The transcription factor CCAAT/enhancer binding protein (C/EBP) family consists of six isoforms. C/EBP␣ is highly expressed in the lung (6) and plays a role in cell proliferation and differentiation in various tissues (17,18), as do C/EBP␤ and C/EBP␦. Given that the newborn lung proliferates and differentiates rapidly, we hypothesized that C/EBP␣ regulates neonatal lung cell proliferation in hyperoxia and during recovery.Here, we demonstrate that C/EBP␣ expression was enhanced in lungs of newborn mice after 72 h of hyperoxia. The increased C/EBP␣ protein was predominantly localized to alveolar type II cells, where altered proliferation was observed. Silencing of C/EBP␣ with a single injection of C/EBP␣ small interfering RNA (siRNA) prior to expo...

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Section: Intrapulmonary Delivery Of C/ebp␣ Sirna Decreases C/ebp␣ Prosupporting

confidence: 90%

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

Guang

Hinson

Bordner

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…If the same effect were present in the small airways, then it could be speculated that changes in Hip influence the thickness of the airway muscle layer and induce more or less airflow limitation. Secondly, a study of POGACH et al [35] demonstrated that several developmental pathways in the lungs of adult mice, including Hh, reactivate for tissue repair following hyperoxia. In addition, others have shown that embryogenic signalling pathways, such as Hh, are activated in human bronchial epithelial cells exposed to cigarette smoke [36].…”

Section: Discussionmentioning

confidence: 99%

Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study

Durme¹,

Eijgelsheim²,

Joos³

et al. 2009

Eur Respir J

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The Hedgehog signalling pathway plays an important role in lung morphogenesis and cellular responses to lung injury. A genome-wide association study has demonstrated that two single nucleotide polymorphisms (SNPs) near the Hedgehog-interacting protein (Hip) gene, SNP identifiers rs1828591 and rs13118928, are associated with risk of chronic obstructive pulmonary disease (COPD). The aim of the present study was to validate the observed association between genetic variation near the Hip gene and COPD, and to investigate whether risk estimates were modified by smoking behaviour.The association between the Hip gene SNPs and COPD was investigated in the Rotterdam Study by logistic regression analyses, adjusted for several covariates. In addition, an association meta-analysis was performed that included data from the genome-wide association study on COPD.Both SNPs were significantly associated with risk of COPD (OR 0.80; 95% CI 0.72-0.91). Homozygosity for the minor G allele resulted in a decreased risk of COPD of ,40% (95% CI 0.47-0.78). There was a significant interaction with the number of pack-years of smoking (p50.004). The meta-analysis yielded an odds ratio for COPD of 0.80 per additional G allele (p53.4610 -9 ).Genetic variation near the Hip gene was significantly associated with risk of COPD, depending on the number of pack-years of smoking.

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“…Ataxin 7 (Atxn7) coding for a relatively ubiquitous protein, is at the top of the list of upregulated genes. Members of the ataxin family have recently been linked to tissue regeneration and epithelial cell repair in several organs, including the skin (52). The gene for the 2d form of calcium-calmodulin-dependent kinase II (CaMKII2d), a strong inducer of cardiac hypertrophy (19), may control keratinocyte proliferation and differentiation, which are calciumdependent processes.…”

Section: Substantial Alterations In the Global Gene Expression Profilmentioning

confidence: 99%

Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse

Terao

Kurosaki

Barzago

et al. 2009

Molecular and Cellular Biology

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The mouse aldehyde oxidase AOH2 (aldehyde oxidase homolog 2) is a molybdoflavoenzyme. Harderian glands are the richest source of AOH2, although the protein is detectable also in sebaceous glands, epidermis, and other keratinized epithelia. The levels of AOH2 in the Harderian gland and skin are controlled by genetic background, being maximal in CD1 and C57BL/6 and minimal in DBA/2, CBA, and 129/Sv strains. Testosterone is a negative regulator of AOH2 in Harderian glands. Purified AOH2 oxidizes retinaldehyde into retinoic acid, while it is devoid of pyridoxal-oxidizing activity. Aoh2 ؊/؊ mice, the first aldehyde oxidase knockout animals ever generated, are viable and fertile. The data obtained for this knockout model indicate a significant role of AOH2 in the local synthesis and biodisposition of endogenous retinoids in the Harderian gland and skin. The Harderian gland's transcriptome of knockout mice demonstrates overall downregulation of direct retinoid-dependent genes as well as perturbations in pathways controlling lipid homeostasis and cellular secretion, particularly in sexually immature animals. The skin of knockout mice is characterized by thickening of the epidermis in basal conditions and after UV light exposure. This has correlates in the corresponding transcriptome, which shows enrichment and overall upregulation of genes involved in hypertrophic responses.Aldehyde oxidases (AOXs) (EC 1.2.3.1) are structurally conserved proteins belonging to the family of molybdoflavoenzymes along with xanthine oxidoreductase (XOR), the key enzyme in the catabolism of purines (25,28). In their catalytically active form, both AOXs and XORs are dimers of identical subunits characterized by three conserved domains separated by nonconserved hinge regions (28). The amino-terminal 25-kDa domain contains two nonidentical 2Fe-2S redox centers. The flavin adenine dinucleotide binding region is located in the intermediate 45-kDa domain, while the substrate and the molybdopterin cofactor binding pocket reside in the carboxy-terminal 85-kDa domain (28). AOXs have broad substrate specificity, hydroxylating N-heterocycles or oxidizing aliphatic as well as aromatic aldehydes into the corresponding acids (35,41,42).The primary structures of mammalian AOXs and XORs are more than 40% identical, and the two types of enzymes are evolutionary related. Most of the available data indicate that AOXs evolved from a primordial form of XOR through a series of gene duplication events (28). In mammals, the number of AOX genes is variable and species specific (25,28,37,65). Rodents have four AOX genes (Aox1, Aoh1, Aoh2, and Aoh3) which are the products of asynchronous duplication events and cluster at a short distance from one another on the same chromosome (chromosome 1c1 in mice and chromosome 9 in rats) (Fig. 1). The Aoh1, Aoh2, and Aoh3 genes are also known as Aox3, Aox4, and Aox3l, respectively, and are currently designated with the latter names in the NCBI database.(The designation of the four mouse AOX genes as Aox1, Aox3, Aox4, and Aox3l in...

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Key developmental regulators change during hyperoxia‐induced injury and recovery in adult mouse lung

Cited by 43 publications

References 59 publications

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study

Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse

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