TGF-β-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung

Nakanishi, Hidehiko; Sugiura, T.; Streisand, James B.; Lonning, Scott; Roberts, Jesse D.

doi:10.1152/ajplung.00389.2006

Cited by 137 publications

(137 citation statements)

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“…Mice were killed at days 1, 7, 14, 21, and 28 after birth for analysis, which spans the period of late lung development in mice. The processing of lung tissue from this model for RNA and protein analysis, as well as immunohistology, has been described previously (20,21), as has the inhibition of TGF-b signaling in mouse pup lungs with a TGF-b1,2,3-neutralizing IgG 1 antibody (1D11; Genzyme, Cambridge, MA) (22). In these studies, an isotype-matched nonimmune IgG 1 antibody (MOPC21; Sigma, St. Louis, MO) did not modulate pulmonary TGF-b signaling.…”

Section: Methods Animal and Tissue Treatmentmentioning

confidence: 99%

“…To explore whether hyperoxia induced abnormal lysyl oxidase expression in the lungs of mouse pups through TGF-b-dependent signaling mechanisms, pups were treated with TGF-b1,2,3-neutralizing antibodies before exposure to 85% oxygen. This has previously been demonstrated to dampen TGF-b signaling in the lungs of 85% oxygen-exposed pups, to improve elastin biogenesis and assembly, and to limit the deleterious effects of hyperoxia on alveologenesis and vasculogenesis (22). Treatment of pups with TGF-b1,2,3-neutralizing antibodies before exposure to 85% oxygen reduced pulmonary lox mRNA expression in the lung, as assessed by semiquantitative RT-PCR ( Figure 6A), as well as quantitative real-time RT-PCR ( Figure 6B).…”

Section: Attenuating Tgf-b Signaling In Vivo Prevents Induction Of Lomentioning

confidence: 98%

“…TGF-b has been broadly implicated in regulating the expression and activity of lysyl oxidases (30,31), and TGF-b signaling is dynamically regulated during mouse and human lung alveolarization (32). Furthermore, TGF-b signaling is abnormally increased in oxygen-injured mouse lungs (20,22). Therefore, the effects of TGF-b, hyperoxia, and combinations thereof, on the expression of lysyl oxidases in fibroblasts (both mouse fibroblast-like NIH/3T3 cells and primary human lung fibroblasts) and paSMC were assessed, because fibroblasts and smooth muscle cells are the primary lysyl oxidase-producing cells (33).…”

Section: Lysyl Oxidases Are Induced By Transforming Growth Factor-b Amentioning

confidence: 99%

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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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Section: Methods Animal and Tissue Treatmentmentioning

confidence: 99%

Section: Attenuating Tgf-b Signaling In Vivo Prevents Induction Of Lomentioning

confidence: 98%

Section: Lysyl Oxidases Are Induced By Transforming Growth Factor-b Amentioning

confidence: 99%

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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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“…The alveolar septal density was determined by investigators masked with respect to the specimen source by dividing the numbers of elastin-containing septa by the parenchymal area using standard methods (17). The mean linear intercept (Lm) was determined using methods detailed in previous work (17)(18)(19)(20). As described in that work, chords less than 8 mm or greater than 250 mm, which represent capillaries and bronchioles, as well as cords that included image margins, were removed from the analysis.…”

Section: Image Capture and Stereologymentioning

confidence: 99%

“…TGF-b signaling plays an important role in normal alveologenesis and is increased in the lungs of newborns with bronchopulmonary dysplasia (18,27,28). Given the role of TGF-b in alveologenesis, we sought to test whether the model system could be used to study pathways involved in secondary septation by introducing neutralizing TGFb antibody into the organ culture system.…”

Section: Tgf-b Contributes To Alveolar Development In Cultured Lungsmentioning

confidence: 99%

A Novel In Vitro Model to Study Alveologenesis

Pieretti¹,

Ahmed

Roberts

et al. 2014

Am J Respir Cell Mol Biol

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Many pediatric pulmonary diseases are associated with significant morbidity and mortality due to impairment of alveolar development. The lack of an appropriate in vitro model system limits the identification of therapies aimed at improving alveolarization. Herein, we characterize an ex vivo lung culture model that facilitates investigation of signaling pathways that influence alveolar septation. Postnatal Day 4 (P4) mouse pup lungs were inflated with 0.4% agarose, sliced, and cultured within a collagen matrix in medium that was optimized to support cell proliferation and promote septation. Lung slices were grown with and without 1D11, an active transforming growth factor-b-neutralizing antibody. After 4 days, the lung sections (designated P4 1 4) and noncultured lung sections were examined using quantitative morphometry to assess alveolar septation and immunohistochemistry to evaluate cell proliferation and differentiation. We observed that the P4 1 4 lung sections exhibited ex vivo alveolarization, as evidenced by an increase in septal density, thinning of septal walls, and a decrease in mean linear intercept comparable to P8, age-matched, uncultured lungs. Moreover, immunostaining showed ongoing cell proliferation and differentiation in cultured lungs that were similar to P8 controls. Cultured lungs exposed to 1D11 had a distinct phenotype of decreased septal density when compared with untreated P4 1 4 lungs, indicating the utility of investigating signaling in these lung slices. These results indicate that this novel lung culture system is optimized to permit the investigation of pathways involved in septation, and potentially the identification of therapeutic targets that enhance alveolarization.

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Aberrant signaling pathways of the lung mesenchyme and their contributions to the pathogenesis of bronchopulmonary dysplasia

Ahlfeld

Conway

2011

Birth Defects Research

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Bronchopulmonary Dysplasia (BPD) is a chronic lung disease in infants born extremely preterm, typically before 28 weeks gestation, characterized by a prolonged need for supplemental oxygen or positive pressure ventilation beyond 36 weeks postmenstrual age. The limited number of autopsy samples available from infants with BPD in the post-surfactant era has revealed a reduced capacity for gas exchange resulting from simplification of the distal lung structure with fewer, larger alveoli due to a failure of normal lung alveolar septation and pulmonary microvascular development. While the mechanisms responsible for alveolar simplification in BPD have not been fully elucidated, mounting evidence suggests that aberrations in the cross-talk between growth factors of the lung mesenchyme and distal airspace epithelium play a key role. Animal models that recapitulate the human condition have expanded our knowledge of the pathology of BPD and have identified candidate matrix components and growth factors in the developing lung that are disrupted by conditions that predispose infants to BPD and interfere with normal vascular and alveolar morphogenesis. This review will focus on the deviations from normal lung development that define the pathophysiology of BPD and summarize the various candidate mesenchymal-associated proteins and growth factors that have been identified as being disrupted in animal models of BPD. Finally, future areas of research to identify novel targets affected in arrested lung development and recovery will be discussed.

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TGF-β-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung

Cited by 137 publications

References 58 publications

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

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

A Novel In Vitro Model to Study Alveologenesis

Aberrant signaling pathways of the lung mesenchyme and their contributions to the pathogenesis of bronchopulmonary dysplasia

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