The Molecular Basis for Abnormal Human Lung Development

Groenman, Freek; Unger, Sharon; Post, Martin

doi:10.1159/000082595

Cited by 74 publications

(42 citation statements)

References 278 publications

(185 reference statements)

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“…Our study suggests that some of the molecular factors that may be involved in generating pulmonary hypoplasia are likely to affect vascular development, exacerbating clinical hypoxemia, the lethal common denominator in this disorder. Other human congenital malformations of the lung that involve pulmonary vascular anomalies (for example alveolar-capillary dysplasia) (Cullaine et al, 1992) are poorly understood molecularly (Groenman et al, 2005). The findings described here may provide an insight into the etiology of these often lethal, congenital diseases.…”

Section: Developmentmentioning

confidence: 68%

Chick pulmonaryWnt5adirects airway and vascular tubulogenesis

Loscertales

Mikels

et al. 2008

Development

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*Wnt5a is an important factor patterning many aspects of early development, including the lung. We find pulmonary non-canonical Wnt5a uses Ror2 to control patterning of both distal air and vascular tubulogenesis (alveolarization). Lungs with mis/overexpressed Wnt5a develop with severe pulmonary hypoplasia associated with altered expression patterns of Shh, L-CAM, fibronectin, VEGF and Flk1. This hypoplastic phenotype is rescued by either replacement of the Shh protein or inhibition of fibronectin function. We find that the effect of Wnt5a on vascular patterning is likely to be through fibronectin-mediated VEGF signaling. These results demonstrate the pivotal role of Wnt5a in directing the essential coordinated development of pulmonary airway and vasculature, by affecting fibronectin levels directly, and by affecting the fibronectin pattern of expression through its regulation of Shh. Data herein suggest that Wnt5a functions in mid-pulmonary patterning (during alveolarization), and is distinct from the Wnt canonical pathway which is more important in earlier lung development.

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Section: Developmentmentioning

confidence: 68%

Chick pulmonaryWnt5adirects airway and vascular tubulogenesis

Loscertales

Mikels

et al. 2008

Development

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“…Notable among these are members of the TGF-b family of peptide growth factors, which are also key regulators of late lung development (45). Recently, excessive TGF-b activity has been identified as a key pathogenic factor in animal models of BPD (20,22,46), which suggested that dysregulated TGF-b signaling might underlie the aberrant expression of lysyl oxidases in BPD. Indeed, dampening of TGF-b signaling in the newborn lung injury model used in this study reduced the expression of the lox gene, although expression of other members of the lysyl oxidase family was unaffected.…”

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Kumarasamy¹,

Schmitt²,

Nave³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

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“…Lung development begins at 3-4 weeks of gestation and occurs in six stages: the embryonic stage (4-7 weeks), pseudoglandular stage (5-17 weeks), canalicular stage (16-26 weeks), saccular stage (24-38 weeks), alveolar stage (36 weeks of gestation to 2 years of life) and microvascular maturation (birth to 2-3 years of age)[25,26,27]. Morotti et al [13,14] postulated that CPAM is caused by a focal arrest in lung development at different stages of the branching of the bronchopulmonary tree: the first subtype (CPAM bronchiolar types I, II and III) at the pseudoglandular stage and the second subtype (CPAM type IV) at the saccular stage.…”

Section: Histopathology and Geneticsmentioning

confidence: 99%

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation

2016

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Congenital pulmonary airway malformation (CPAM) is one of the most common lung lesions detected prenatally. Despite the research efforts made in the past few years, controversy and lack of clarity in the literature still exist regarding nomenclature, classification, pathogenesis and the management of CPAM. Therefore, it is of greatest importance to delineate the natural history of CPAMs and to create a consensus to guide the management and follow-up of these lesions. This review will focus on classification systems, highlighting the most recent advancements in pathogenesis, and current practice in the prenatal diagnosis of CPAM. Strategies of prenatal management and postnatal management will be reviewed. Long-term follow-up, including lung cancer risk, is discussed and an outcome perspective is presented.

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The Molecular Basis for Abnormal Human Lung Development

Cited by 74 publications

References 278 publications

Chick pulmonaryWnt5adirects airway and vascular tubulogenesis

Chick pulmonaryWnt5adirects airway and vascular tubulogenesis

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Prenatal and Postnatal Management of Congenital Pulmonary Airway Malformation

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