Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Shifren, Adrián; Durmowicz, Anthony G.; Knutsen, Russell H.; Hirano, Eiichi; Mecham, Robert P.

doi:10.1152/ajplung.00352.2006

Cited by 89 publications

(88 citation statements)

References 57 publications

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“…The severity of the phenotype may depend on gene dosage of total fibulins instead of the presence or absence of specific fibulin proteins. Our laboratory has recently shown that mice with decreasing amounts of elastin (from 100 to 30% normal levels) have increasingly severe vascular (Hirano et al, 2007) and pulmonary (Shifren et al, 2007) phenotypes. If elastin amounts fall below 30%, the mice cannot survive postnatally (Hirano et al, 2007).…”

Section: Coordinated Gene Expressionmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

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355

354

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Elastic fibers provide recoil to tissues that undergo repeated stretch, such as the large arteries and lung. These large extracellular matrix (ECM) structures contain numerous components, and our understanding of elastic fiber assembly is changing as we learn more about the various molecules associated with the assembly process. The main components of elastic fibers are elastin and microfibrils. Elastin makes up the bulk of the mature fiber and is encoded by a single gene. Microfibrils consist mainly of fibrillin, but also contain or associate with proteins such as microfibril associated glycoproteins (MAGPs), fibulins, and EMILIN-1. Microfibrils were thought to facilitate alignment of elastin monomers prior to cross-linking by lysyl oxidase (LOX). We now know that their role, as well as the overall assembly process, is more complex. Elastic fiber formation involves elaborate spatial and temporal regulation of all of the involved proteins and is difficult to recapitulate in adult tissues. This report summarizes the known interactions between elastin and the microfibrillar proteins and their role in elastic fiber assembly based on in vitro studies and evidence from knockout mice. We also propose a model of elastic fiber assembly based on the current data that incorporates interactions between elastin, LOXs, fibulins and the microfibril, as well as the pivotal role played by cells in structuring the final functional fiber. Birth Defects Research (Part C) 81:229-240,

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Section: Coordinated Gene Expressionmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

Self Cite

355

354

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“…Using genetically modified mouse strains that express elastin at different levels, it was recently shown that not only lung development was adversely affected in mice with lowest levels, and further, that animals with intermediate levels, although initially developing normal alveoli, developed worse emphysema than mice with normal levels when exposed to cigarette smoke [39]. An emphysema-like phenotype has also been described in mice lacking LOX [40], fibrillin-1 [41] or fibulin-5 [42].…”

Section: Elastic Fiber Destruction and Disrupted Assemblymentioning

confidence: 99%

“…), and better understanding these represents a challenge to optimize the therapeutic use of retinoids. [107,108] Mechanical injury + ± [1,4] Infections ± - [1] Directly associated genetic disorders -+ [3] Risk-associated gene polymorphisms + + [2] Histological features Airspace enlargement + + [1][2][3][4] Elastic fiber destruction/ disrupted assembly + + [37][38][39][40][41] Extracellular matrix remodeling + + [1][2][3][4] Diminished microvasular bed ± + [52][53][54] Dysmorphic capillary vessels + -…”

Section: Relative Inefficiency Of Retinoidsmentioning

confidence: 99%

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Bourbon

Boucherat

Boczkowski

et al. 2009

Trends in Molecular Medicine

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“…Two sections from each of one to two blocks of right upper lung lobe tissue per animal in the study were stained with hematoxylin and eosin. Ten digital images at 200ϫ magnification per section were captured using a random starting point and a random number generator, and then analyzed for chord length using NIH Image software (Version 1.63, National Institutes of Health, Bethesda, MD) with a chord length macro (available at http://rsb.info.nih.gov/nih-image) (21). Tissue density was calculated by assessing air space and tissue using Image Pro Plus software and the formula: Tissue density ϭ area occupied by tissue/total area (tissue ϩ air space).…”

Section: Animalsmentioning

confidence: 99%

Retinoids Increase Lung Elastin Expression But Fail to Alter Morphology or Angiogenesis Genes in Premature Ventilated Baboons

et al. 2007

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Retinoids regulate elastin synthesis by alveolar myofibroblasts and affect angiogenesis pathways, both of which are processes critical for alveolar development. Retinoids accelerate alveolarization in rodents and are now used therapeutically in premature infants at risk of bronchopulmonary dysplasia (BPD). This study examined the effects of retinoid supplementation on alveolar elastin expression and deposition and angiogenesis-related signaling in a primate model of BPD. Premature baboons delivered at 125 d of gestation after maternal steroid treatment were given surfactant and ventilated with minimal supplemental oxygen for 14 d with (n ϭ 5) and without (n ϭ 5) supplemental vitamin A (5000 U/kg/d) and compared with 140-d unventilated controls. Ventilatory efficiency index (VEI) and oxygenation index (OI) were not statistically different between ventilated treatment groups. Expression of vascular endothelial growth factor A (VEGF-A), fms-related tyrosine kinase 1 (Flt-1), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) was repressed by premature delivery and mechanical ventilation and was not altered by retinoid supplementation. Retinoid supplementation did not enhance alveolar angiogenesis. Elastin expression was repressed by premature delivery and extended ventilation, and retinoid supplementation increased elastin expression specifically in alveolar myofibroblasts within alveolar walls. These results suggest that the small decrease in mortality among premature infants receiving retinoid supplementation may not be mediated through enhanced alveolar development. M any premature infants develop respiratory distress and often require mechanical ventilation and supplemental oxygen to survive. These interventions can perpetuate injury and ultimately lead to altered lung architecture BPD (1), with failed alveolar development, which is a hallmark of BPD (2). The incidence of BPD remains high in infants of very low birth weight despite advancements such as surfactant therapy.The findings that retinoid signaling is required for alveolar development in mice and that retinoid treatment can enhance alveolar development in rats (3-5) led to vitamin A supplementation of preterm infants at risk of BPD. Some clinical trials of vitamin A supplementation in premature infants have shown no benefit, and others have found that dose is critical (6 -8). Tyson et al. (9) found that overall, one additional infant survived without chronic lung disease for every 14 -15 infants who received vitamin A supplements . The mechanism by which vitamin A supplementation may reduce BPD or mortality is not well defined, but may be linked to enhanced alveolar development.The altered alveolar capillary network associated with BPD (10 -12) supports the "vascular hypothesis" that failed capillary development is central to the pathogenesis of BPD (13). Retinoid signaling is required for alveolar capillary development. Vitamin A supplementation may decrease the incidence of BPD by stimulating VEGF expression in alv...

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Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Abstract: Shifren A, Durmowicz AG, Knutsen RH, Hirano E, Mecham RP. Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema.

Cited by 89 publications

References 57 publications

New insights into elastic fiber assembly

New insights into elastic fiber assembly

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

Retinoids Increase Lung Elastin Expression But Fail to Alter Morphology or Angiogenesis Genes in Premature Ventilated Baboons

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