Human Umbilical Cord Blood Mononuclear Cells in a Double-Hit Model of Bronchopulmonary Dysplasia in Neonatal Mice

Monz, Dominik; Tutdibi, Erol; Mildau, Céline; Shen, Jie; Kasoha, Mariz; Laschke, Matthias W.; Roolfs, Torge; Schmiedl, Andreas; Tschernig, Thomas; Bieback, Karen; Gortner, Ludwig

doi:10.1371/journal.pone.0074740

Cited by 37 publications

(46 citation statements)

References 46 publications

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“…Although some genes with an HRE can be increased by other signaling pathways [for example VEGF mRNA can be increased by IGF1 (13)], this does not appear to be the case here because, in this model, the chronic hypoxemia did not increase IGF1 mRNA. However, an increase in IGF1 mRNA was found in the lung of mice that were exposed to hypoxia and then hyperoxia in the neonatal period (55). Interestingly, these mice also had a decrease in SP-B and -C mRNA expression and no change in VEGF or TGF-␤ mRNA expression but a decrease in MTOR mRNA expression, which is downstream of the IGF1R (55).…”

Section: Resultsmentioning

confidence: 99%

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Orgeig

McGillick

Botting

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130-135 (n = 19) and 139-145 (n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain (PHD)2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α (HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.

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Section: Resultsmentioning

confidence: 99%

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Orgeig

McGillick

Botting

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Compared with mice exposed to prenatal normoxia, the prenatal hypoxia mice were born at decreased weight, which mimics intrauterine growth restriction seen in many preterm infants (31). Mice in the "double-hit" model subsequently treated with umbilical cord mononuclear cells at PN day 7 showed decreased inflammatory markers such as IL-1␤ compared with untreated double-hit mice and normalization of alveolar septal thickness compared with normoxic controls (57).…”

Section: Rodent Models Of Pulmonary Diseasementioning

confidence: 98%

Animal models of bronchopulmonary dysplasia. The term mouse models

Berger

Bhandari

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

220

168

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Berger J, Bhandari V. Animal models of bronchopulmonary dysplasia. I. The term mouse models. Am J Physiol Lung Cell Mol Physiol 307: L936 -L947, 2014. First published October 10, 2014 doi:10.1152/ajplung.00159.2014.-The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante-and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation-induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD.

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“…IGF-1 has also been found to play a role in chronic lung disease, such as respiratory distress syndrome and bronchopulmonary dysplasia, of premature and newborn infants (see Refs. [29][30][31][32][33][34]. However, the exact role of IGF-1 in pulmonary SMC proliferation, differentiation, and structural remodeling of vessels leading to the pathogenesis of PH sequelae has not been fully established.…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

Sun¹,

Ramchandran²,

Chen

et al. 2016

Am J Respir Cell Mol Biol

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Insulin-like growth factor (IGF)-1 is a potent mitogen of vascular smooth muscle cells (SMCs), but its role in pulmonary vascular remodeling associated with pulmonary hypertension (PH) is not clear. In an earlier study, we implicated IGF-1 in the pathogenesis of hypoxia-induced PH in neonatal mice. In this study, we hypothesized that hypoxia-induced up-regulation of IGF-1 in vascular smooth muscle is directly responsible for pulmonary vascular remodeling and PH. We studied neonatal and adult mice with smooth muscle-specific deletion of IGF-1 and also used an inhibitor of IGF-1 receptor (IGF-1R), OSI-906, in neonatal mice. We found that, in neonatal mice, SMC-specific deletion of IGF-1 or IGF-1R inhibition with OSI-906 attenuated hypoxia-induced pulmonary vascular remodeling in small arteries, right ventricular hypertrophy, and right ventricular systolic pressure. Pulmonary arterial SMCs from IGF-1-deleted mice or after OSI-906 treatment exhibited reduced proliferative potential. However, in adult mice, smooth muscle-specific deletion of IGF-1 had no effect on hypoxia-induced PH. Our data suggest that vascular smooth muscle-derived IGF-1 plays a critical role in hypoxia-induced PH in neonatal mice but not in adult mice. We speculate that the IGF-1/IGF-1R axis is important in pathogenesis of PH in the developing lung and may be amenable to therapeutic manipulation in this age group.Keywords: insulin-like growth factor; pulmonary hypertension; vascular smooth muscle; neonatal; hypoxia Clinical RelevanceWhat this study adds to the field: Using conditional gene deletion in mice, this study shows that loss of insulin-like growth factor (IGF)-1 in smooth muscle cells protects against hypoxia-induced pulmonary vascular remodeling, right ventricular hypertrophy (RVH), and pulmonary hypertension (PH) in neonatal mice. Inhibition of IGF-1 receptor (IGF-1R) with OSI-906 diminished hypoxia-induced RVH and pulmonary vascular remodeling in neonatal mice, indicating that targeting the IGF-1/IGF-1R axis may have therapeutic benefits in the treatment of hypoxic PH in that age group. Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure accompanied by pulmonary vascular remodeling, leading to right ventricular hypertrophy (RVH) and failure. Proliferation and migration of smooth muscle cells (SMCs) is a characteristic feature of pulmonary vascular remodeling in PH, and dysregulation of many growth factors have been implicated in this process (1, 2). Several growth factors have been implicated in the vascular remodeling and pathogenesis of pulmonary arterial hypertension, and their definitive functions are still being unraveled (reviewed in Refs. 1, 3, 4). Insulin-like growth factor (IGF)-1 is a member of the insulin/IGF family and plays a crucial role in the growth, differentiation, and postnatal development of many tissues and in the regulation of overall growth and metabolism of an organism. IGF-1 is a single-chain polypeptide with a high sequence homology to proinsulin and ...

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Human Umbilical Cord Blood Mononuclear Cells in a Double-Hit Model of Bronchopulmonary Dysplasia in Neonatal Mice

Cited by 37 publications

References 46 publications

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

Animal models of bronchopulmonary dysplasia. The term mouse models

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

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