The role of integrin α8β1 in fetal lung morphogenesis and injury

Benjamin, John T.; Gaston, David C; Halloran, Brian; Schnapp, Lynn M.; Zent, Roy; Prince, Lawrence S.

doi:10.1016/j.ydbio.2009.09.021

Cited by 44 publications

(47 citation statements)

References 45 publications

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“…If increased BMP/Smad signaling in Fstl1 −/− lung plays a causative role in the development of atelectasis, it is expected that reducing BMP signaling would ameliorate or even rescue the atelectasis in Fstl1 −/− lungs. To test this possibility, we used an E15.5 embryonic mouse lung explant model of saccular stage development (24) and added Noggin, an antagonist of BMP ligand, to reduce BMP signaling activity. After 48 to 54 h of ex vivo culture, sections of Fstl1 −/− explants showed condensed/atelectatic phenotype with 54% less dilation of saccular airways compared with WT controls (Fig.…”

Section: Reducing Bmp Signaling Activity Rescues Pulmonary Atelectasimentioning

confidence: 99%

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development

Geng

Dong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

198

273

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Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-β/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module–containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1 -deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1 -deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.

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Section: Reducing Bmp Signaling Activity Rescues Pulmonary Atelectasimentioning

confidence: 99%

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development

Geng

Dong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

198

273

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“…22 Briefly, after rehydration, paraffin-embedded lung sections were incubated overnight with resorcin-fuchsin (Electron Microscopy Sciences) to stain elastic fibers. Counterstaining of elastin-stained sections was performed using tartrazine in saturated picric acid (Electron Microscopy Sciences).…”

Section: Hart's Elastin Stainingmentioning

confidence: 99%

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

Benjamin

Meer

et al. 2016

The American Journal of Pathology

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The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory kB kinase b transactivated) mice that conditionally express an activator of the NF-kB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-kB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase likee1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory kB kinase b transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-kB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

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“…Recently, lung hypoplasia due to integrin α3 mutations has been identified as a cause of early childhood mortality (Has et al, 2012;Nicolaou et al, 2012). The RGD-binding integrin α8β1 has also been shown to regulate lung development as constitutive integrin α8-null mice have abnormally fused medial and caudal lobes of the lung, as well as subtle abnormalities in airway division (Benjamin et al, 2009). β1 integrin is the major isoform of the eight β-integrin subunits, and is the β-integrin subunit present in 12 of the 24 known α-β integrin heterodimers (Pozzi and Zent, 2011).…”

Section: Introductionmentioning

confidence: 99%

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

et al. 2014

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Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophagemediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.

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The role of integrin α8β1 in fetal lung morphogenesis and injury

Cited by 44 publications

References 45 publications

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

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