A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD

Brandsma, Corry‐Anke; Berge, Maarten van den; Postma, Dirkje S.; Jonker, Marnix; Brouwer, Sharon; Paré, Peter D.; Sin, Don D.; Bossé, Yohan; Laviolette, Michel; Karjalainen, Juha; Fehrmann, Rudolf S.N.; Nickle, David C.; Hao, Ke; Spanjer, Anita I.R.; Timens, Wim; Franke, Lude

doi:10.1136/thoraxjnl-2014-205091

Cited by 95 publications

(97 citation statements)

References 34 publications

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“…MFAP4 has previously been proposed to mechanistically affect elastogenesis or maintenance of ECM fiber integrity (4,45). Our observations did not fully support the original suggestions as we found identical elastin contents in Mfap4 ϩ/ϩ and Mfap4 Ϫ/Ϫ mice under physiological conditions.…”

Section: Discussioncontrasting

confidence: 54%

Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4

Holm

Wulf-Johansson

Hvidsten

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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protein 4 (MFAP4) is localized to elastic fibers in blood vessels and the interalveolar septa of the lungs and is further present in bronchoalveolar lavage. Mfap4 has been previously suggested to be involved in elastogenesis in the lung. We tested this prediction and aimed to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4-deficient (Mfap4 Ϫ/Ϫ ) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4 Ϫ/Ϫ mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated microcomputed tomography (micro-CT) in 8-mo-old Mfap4 Ϫ/Ϫ mice, we found that the mean density of the lung parenchyma was decreased, and the low-attenuation area (LAA) was significantly increased by 14% compared with Mfap4 ϩ/ϩ mice. Transmission electron microscopy (TEM) did not reveal differences in the organization of elastic fibers, and there was no difference in elastin content, but a borderline significant increase in elastin mRNA expression in 3-mo-old mice. Stereological analysis showed that alveolar surface density in relation to the lung parenchyma and total alveolar surface area inside of the lung were both significantly decreased in Mfap4 Ϫ/Ϫ mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4 Ϫ/Ϫ mice. However, Mfap4 Ϫ/Ϫ mice developed a spontaneous loss of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes.air space enlargement; gene deficiency; MFAP4 MFAP4 IS A 36-KDA GLYCOPROTEIN composed of a short NH 2 -terminal region comprising one cysteine residue and an ArgGly-Asp (RGD) integrin-binding motif, followed by a COOHterminal fibrinogen-related domain (FReD) (51). The MFAP4 protein is a disulfide-linked dimer that forms higher homooligomeric structures via noncovalent interactions (26,38). FReDs are found in various human proteins involved in distinct functions, including innate immunity, tissue growth, and remodeling (43).MFAP4 is considered to be the human homolog to a 36-kDa microfibril-associated glycoprotein (MAGP-36) originally found to be localized to the elastin-microfibril interface in the porcine aorta (23). MFAP4 was later detected in a variety of both elastic and nonelastic tissues in various species

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Section: Discussioncontrasting

confidence: 54%

Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4

Holm

Wulf-Johansson

Hvidsten

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It has been shown previously, that MMP-12 −/-mice are protected from the development of cigarette smoke (CS)-induced emphysema via a reduction in elastin fragment generation and thus, less monocyte chemotactic activity in BALF of these mice compared to control [25]. Recent studies have further highlighted reduced lysyl oxidase expression and fibulin-5 activity contributing to impaired elastic fibre assembly and repair in COPD patients [40,41]. In this context, a reduction of tropoelastin might reduce the number of misassembled elastin fibres (and therefore reduce protein overload) and the potential source of monocyte chemotactic activity.…”

Section: Discussionmentioning

confidence: 99%

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage ( per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs. @ERSpublications Patient-derived 3D-LTCs are a powerful tool for preclinical drug validation and imaging of Wnt-induced lung repair

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“…Moreover, recent in silico analysis predicted that Mfap4 deficiency can result in abnormal vascular physiology. 18 These observations suggest that MFAP4 potentially plays an important role in VSMC biology and vascular remodeling.…”

mentioning

confidence: 98%

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Schlosser¹,

Pilecki²,

Hemstra³

et al. 2016

ATVB

101

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V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.

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A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD

Cited by 95 publications

References 34 publications

Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4

Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

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