Hypoxia-inducible Factors in the First Trimester Human Lung

Groenman, Freek; Rutter, Martin; Caniggia, Isabella; Tibboel, Dick; Post, Martin

doi:10.1369/jhc.6a7129.2006

Cited by 55 publications

(50 citation statements)

References 39 publications

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“…HIF complex is a heterodimer composed of one of three α-subunits (HIF-1α, HIF-2α, or HIF-3α) and a β-subunit (ARNT; also known as aryl hydrocarbon receptor nuclear translocator). In fetal lung, HIF mRNA and protein levels are quite high [26,32,34], being the HIF-1α protein localized predominantly in the branching epithelium [34]. These authors showed that induction of HIF-1 protein in fetal lung buds was sufficient to induce lung development even under non-hypoxic conditions, whereas its depletion, using antisense oligonucleotides, reduced lung branching morphogenesis and vascularization [35].…”

Section: Discussionmentioning

confidence: 99%

The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

Granja

Morais-Santos²,

Miranda-Gonçalves³

et al. 2013

Cell Physiol Biochem

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Background/Aims: The human embryo develops in a hypoxic environment. In this way, cells have to rely on the glycolytic pathway for energy supply, leading to an intracellular accumulation of monocarboxylates such as lactate and pyruvate. These acids have an important role in cell metabolism and their rapid transport across the plasma membrane is crucial for the maintenance of intracellular pH homeostasis. This transport is mediated by a family of transporters, designated by monocarboxylate transporters (MCTs), namely isoforms 1 and 4. MCT1/4 expression is regulated by the ancillary protein CD147.The general aim of this study was to characterize the expression pattern of MCT1/4, CD147 and the glucose transporter GLUT1 during human fetal lung development and elucidate the role of MCTs in lung development. Methods: The expression pattern of MCT1/4 and GLUT1 was characterized by immunohistochemistry and fetal lung viability and branching were evaluated by exposing rat fetal lung explants to CHC, an inhibitor of MCT activity. Results: Our findings show that all the biomarkers are differently expressed during fetal lung development and that CHC appears to have an inhibitory effect on lung branching and viability, in a dose dependent way. Conclusion: We provide evidence for the role of MCTs in embryo lung development, however to prove the dependence of MCT activity further studies are waranted.

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Section: Discussionmentioning

confidence: 99%

The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

Granja

Morais-Santos²,

Miranda-Gonçalves³

et al. 2013

Cell Physiol Biochem

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“…Five-micron random lung tissue sections were mounted onto Superfrost slides (VWR International, West Chester, PA, USA). Immunohistochemistry of HIF-1a was then performed as previously described [26]. Additional details of the methods are provided in the online supplementary material.…”

Section: Immunohistochemistry Of Hif-1amentioning

confidence: 99%

Hypoxia inducible factor-1α in human emphysema lung tissue

Matsumura¹,

Mizuno²,

Kraskauskas³

et al. 2010

Eur Respir J

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The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1a in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n56; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n513; stage III and IV).We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1a and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1a and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1a protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1a protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry.In conclusion, reduced expression of HIF-1a protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.

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“…However, decreases in alveolar O 2 tensions (pulmonary hypoxia) can result from a number of pathological conditions, including chronic obstructive pulmonary disease, lung cancers, and pulmonary hypertension and edema (34). In contrast, differentiation and development of the fetal lung distal epithelium normally occurs in low O 2 (1-5% O 2 ) (19), with hypoxia-related signaling in the pulmonary epithelium throughout gestation (8,9,28). This condition is critical for normal fetal lung development and preparation for breathing after birth (1, 32).…”

mentioning

confidence: 99%

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

Lottes

Newton

Spyropoulos

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lottes RG, Newton DA, Spyropoulos DD, Baatz JE. Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation. Am J Physiol Lung Cell Mol Physiol 306: L947-L955, 2014. First published March 28, 2014 doi:10.1152/ajplung.00298.2013.-Although many lung diseases are associated with hypoxia, alveolar type II epithelial (ATII) cell impairment, and pulmonary surfactant dysfunction, the effects of O 2 limitation on metabolic pathways necessary to maintain cellular energy in ATII cells have not been studied extensively. This report presents results of targeted assays aimed at identifying specific metabolic processes that contribute to energy homeostasis using primary ATII cells and a model ATII cell line, mouse lung epithelial 15 (MLE-15), cultured in normoxic and hypoxic conditions. MLEs cultured in normoxia demonstrated a robust O 2 consumption rate (OCR) coupled to ATP generation and limited extracellular lactate production, indicating reliance on oxidative phosphorylation for ATP production. Pharmacological uncoupling of respiration increased OCR in normoxic cultures to 175% of basal levels, indicating significant spare respiratory capacity. However, when exposed to hypoxia for 20 h, basal O2 consumption fell to 60% of normoxic rates, and cells maintained only ϳ50% of normoxic spare respiratory capacity, indicating suppression of mitochondrial function, although intracellular ATP levels remained at near normoxic levels. Moreover, while hypoxic exposure stimulated glycogen synthesis and storage in MLE-15, glycolytic rate (as measured by lactate generation) was not significantly increased in the cells, despite enhanced expression of several enzymes related to glycolysis. These results were largely recapitulated in murine primary ATII, demonstrating MLE-15 suitability for modeling ATII metabolism. The ability of ATII cells to maintain ATP levels in hypoxia without enhancing glycolysis suggests that these cells are exceptionally efficient at conserving ATP to maintain bioenergetic homeostasis under O 2 limitation. mitochondrial function; metabolism THE ALVEOLAR EPITHELIUM FORMS the barrier between the pulmonary vasculature and the external milieu and serves as the surface across which O 2 and waste gases are exchanged. Because of their physical location, the cells that line alveoli in developed human lungs are normally exposed to an exceptionally well-oxygenated environment of ϳ13% O 2 in nondiseased lungs (i.e., a PO 2 of ϳ105 mmHg compared with a PO 2 of ϳ40 mmHg in peripheral blood) (33). However, decreases in alveolar O 2 tensions (pulmonary hypoxia) can result from a number of pathological conditions, including chronic obstructive pulmonary disease, lung cancers, and pulmonary hypertension and edema (34). In contrast, differentiation and development of the fetal lung distal epithelium normally occurs in low O 2 (1-5% O 2 ) (19), with hypoxia-related signaling in the pulmonary epithelium throughout gestation (8,9,28). This condition is critical for normal fetal lung ...

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Hypoxia-inducible Factors in the First Trimester Human Lung

Cited by 55 publications

References 39 publications

The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

Hypoxia inducible factor-1α in human emphysema lung tissue

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

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