The Stumbling Block in Lung Repair of Emphysema: Elastic Fiber Assembly

Shifren, Adrián

doi:10.1513/pats.200601-009aw

Cited by 126 publications

(108 citation statements)

References 54 publications

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“…In emphysema, where the mature elastin scaffold is disrupted, a similar compensatory increase in the production of elastin occurs, 39,40 but developmental programs required for correct assembly of elastic fibers are not activated, and structural integrity of the lung remains impaired. 41 Fibulin-5 is an important adaptor molecule in the elastin assembly process. Along with tropoelastin, which forms the amorphous core in elastic fibers, the short fibulins, fibulin 4 and 5, are components critical for the assembly of ECM components.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…It is widely accepted that fibrillar proteins, such as collagens and fibronectins, account for the tensile strength of the lung, whereas elastin molecules account for the elastic recoil (23,24). Modifications in the levels and ratios of these proteins (among others) thus alter relative contributions of each molecule to ECM stiffness.…”

Section: Modulation Of Ecm Stiffnessmentioning

confidence: 99%

Lung Extracellular Matrix and Fibroblast Function

2015

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Extracellular matrix (ECM) is a tissue-specific macromolecular structure that provides physical support to tissues and is essential for normal organ function. In the lung, ECM plays an active role in shaping cell behavior both in health and disease by virtue of the contextual clues it imparts to cells. Qualities including dimensionality, molecular composition, and intrinsic stiffness all promote normal function of the lung ECM. Alterations in composition and/or modulation of stiffness of the focally injured or diseased lung ECM microenvironment plays a part in reparative processes performed by fibroblasts. Under conditions of remodeling or in disease states, inhomogeneous stiffening (or softening) of the pathologic ECM may both precede modifications in cell behavior and be a result of disease progression. The ability of ECM to stimulate further ECM production by fibroblasts and drive disease progression has potentially significant implications for mesenchymal stromal cell-based therapies; in the setting of pathologic ECM stiffness or composition, the therapeutic intent of progenitor cells may be subverted. Taken together, current data suggest that lung ECM actively contributes to health and disease; thus, mediators of cell-ECM signaling or factors that influence ECM stiffness may represent viable therapeutic targets in many lung disorders.

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“…This is followed by a decrease in expression to low levels that persist through adulthood (Kelleher et al, 2004). In adult tissue, elastic fibers are difficult to repair and elastin often does not polymerize or form functional three-dimensional (3D) fibers (Chrzanowski et al, 1980;Shifren and Mecham, 2006). This is probably because the complicated temporal and spatial regulation is difficult to recapitulate in adult tissues.…”

Section: Coordinated Gene Expressionmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

358

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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The Stumbling Block in Lung Repair of Emphysema: Elastic Fiber Assembly

Cited by 126 publications

References 54 publications

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

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

Lung Extracellular Matrix and Fibroblast Function

New insights into elastic fiber assembly

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