Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A

Sucre, Jennifer M.S.; Vickers, Kasey C.; Benjamin, John T.; Plosa, Erin J.; Jetter, Christopher S.; Cutrone, Alissa; Ransom, Meaghan; Anderson, Zachary; Sheng, Quanhu; Fensterheim, Benjamin A.; Ambalavanan, Namasivayam; Millis, Bryan A.; Lee, Ethan; Zijlstra, Andries; Königshoff, Mélanie; Blackwell, Timothy S.; Guttentag, Susan H.

doi:10.1164/rccm.201908-1513oc

Cited by 58 publications

(55 citation statements)

References 44 publications

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“…It is also notable that several independent datasets from emphysema patients, in which repair capacity is diminished, show significant downregulation of VANGL2 and WNT5A (Ezzie et al, 2012;Poobalasingam et al, 2017;Zhang et al, 2020). However, contradictory findings with regard to pro-repair/migratory (Witze et al, 2008;Vuga et al, 2009;Gao et al, 2011;Poobalasingam et al, 2017;Yuan et al, 2019;Li et al, 2020;Zhang et al, 2020) or anti-repair effects (Baarsma et al, 2017;Wu et al, 2019;Sucre et al, 2020) of WNT5A suggest that the complex mechanism of action of WNT5A may be cell type or tissue context-dependent or may differ depending on the balance between PCP and other signaling pathways, such as canonical Wnt signaling. Thus, it will be important to carry out further detailed investigation of how WNT5A stimulates repair in Vangl2 Lp/+ mice.…”

Section: Discussionmentioning

confidence: 99%

“…WNT5A is a current target of interest for treatment of several lung diseases in which there is aberrant expression of this ligand including: chronic obstructive pulmonary disease (COPD)/emphysema, idiopathic pulmonary arterial hypertension (IPAH), bronchopulmonary dysplasia (BPD), and interstitial pneumonia (UIP) (Vuga et al, 2009;Baarsma et al, 2017;Yuan et al, 2019;Li et al, 2020;Sucre et al, 2020;Vladar and Königshoff, 2020). In addition, WNT5A has an important role in progenitor cell induction following lung injury (Nabhan et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

Cheong

Akram

Matellan

et al. 2020

Front. Cell Dev. Biol.

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VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The Vangl2 Lp mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from Vangl2 Lp/+ mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. Vangl2 Lp/+ tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in Vangl2 Lp/+ TECs. YAP signaling in Vangl2 Lp airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in Vangl2 Lp/+ , confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

Cheong

Akram

Matellan

et al. 2020

Front. Cell Dev. Biol.

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“…Precision cut lung slices (PCLS) were made from neonatal mouse lungs at PN5 or PN12 or from adult mouse lungs using previously published methods (62,63). Briefly, after euthanasia, lungs were perfused with cold phosphate buffered saline after which a blunt-tipped catheter was inserted into the trachea.…”

Section: Precision Cut Lung Slicesmentioning

confidence: 99%

“…RNAscope (ACD) was used to perform RNA in situ hybridization (RNA ISH) according to the manufacturer's instructions as previously described (63,65). RNAscope probes to the following mouse genes were used for experiments -Fbln5 (Cat# 493621, ACD) and Eln (Cat # 319361, ACD).…”

Section: Rna In Situ Hybridization and Immunofluorescence Imagingmentioning

confidence: 99%

Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD

Benjamin¹,

Plosa²,

Sucre³

et al. 2021

Journal of Clinical Investigation

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Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage [postnatal day (PN)3-PN5] but not alveolar stage (PN10-PN12) of lung development disrupts elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progresses through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, both purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation down-regulated elastin and fibulin-5 expression by saccular stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. While neutrophils play a wellrecognized role in COPD development in adults, neutrophilic inflammation may also contribute to early life predisposition to COPD.

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“…In addition, increased mesenchymal Wnt5A during the saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening in BPD. Wnt5A inhibition abrogates the BPD transcriptomic phenotype induced by hyperoxia [ 71 ].…”

Section: Deregulated Signaling Pathwaysmentioning

confidence: 99%

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

Mathew

2020

Children

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The alveolar and vascular developmental arrest in the premature infants poses a major problem in the management of these infants. Although, with the current management, the survival rate has improved in these infants, but bronchopulmonary dysplasia (BPD) is a serious complication associated with a high mortality rate. During the neonatal developmental period, these infants are vulnerable to stress. Hypoxia, hyperoxia, and ventilation injury lead to oxidative and inflammatory stress, which induce further damage in the lung alveoli and vasculature. Development of pulmonary hypertension (PH) in infants with BPD worsens the prognosis. Despite considerable progress in the management of premature infants, therapy to prevent BPD is not yet available. Animal experiments have shown deregulation of multiple signaling factors such as transforming growth factorβ (TGFβ), connective tissue growth factor (CTGF), fibroblast growth factor 10 (FGF10), vascular endothelial growth factor (VEGF), caveolin-1, wingless & Int-1 (WNT)/β-catenin, and elastin in the pathogenesis of BPD. This article reviews the signaling pathways entailed in the pathogenesis of BPD associated with PH and the possible management.

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Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A

Cited by 58 publications

References 44 publications

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD

Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

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