Transglutaminase 2: a new player in bronchopulmonary dysplasia?

Witsch, Thilo Jörn; Niess, Gero; Sakkas, Elpidoforos; Likhoshvay, T.; Becker, Simone; Herold, Susanne; Mayer, Konstantin; Vadász, István; Roberts, Jesse D.; Seeger, Werner; Morty, Rory E.

doi:10.1183/09031936.00075713

Cited by 28 publications

(21 citation statements)

References 30 publications

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“…Against this background, transglutaminases were addressed in the present study, given earlier reports of increased lung TGM2 expression in clinical and experimental BPD . The data reported in the present study indicate that TGM2 does play a role in normal lung development, since Tgm2 −/− mice exhibited an increased septal thickness, and a decreased gas‐exchange surface area.…”

Section: Discussionmentioning

confidence: 65%

“…TGM2 has also been implicated in lung diseases, including lung fibrosis [26,27], cystic fibrosis [28], pulmonary hypertension [29][30][31] and airway inflammation [32,33]. The observation that TGM2 expression changes over the course of lung alveolarization in rats [34,35] is noteworthy, given that TGM2 lung steady-state mRNA and protein levels are increased in preterm infants that died with BPD [18]. Furthermore, steady-state Tgm2 mRNA and TGM2 protein levels were elevated in mouse lungs in experimental BPD, where increased N e -(c-L-glutamyl)-L-lysine cross-link immunoreactivity was also noted.…”

Section: Introductionmentioning

confidence: 99%

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Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

et al. 2018

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The generation, maturation and remodelling of the extracellular matrix (ECM) are essential for the formation of alveoli during lung development. Alveoli formation is disturbed in preterm infants that develop bronchopulmonary dysplasia (BPD), where collagen fibres are malformed, and perturbations to lung ECM structures may underlie BPD pathogenesis. Malformed ECM structures might result from abnormal protein cross-linking, in part attributable to the increased expression and activity of transglutaminase 2 (TGM2) that have been noted in affected patient lungs, as well as in hyperoxia-based BPD animal models. The objective of the present study was to assess whether TGM2 plays a causal role in normal and aberrant lung alveolarization. Targeted deletion of Tgm2 in C57BL/6J mice increased septal thickness and reduced gas-exchange surface area in otherwise normally developing lungs. During aberrant lung alveolarization that occurred under hyperoxic conditions, collagen structures in Tgm2 mice were partially protected from the impact of hyperoxia, where normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance was restored; however, the lung alveolar architecture remained abnormal. Inhibition of transglutaminases (including TGM2) with cysteamine appreciably reduced transglutaminase activity in vivo, as assessed by N -(γ-l-glutamyl)-l-lysine abundance and TGM catalytic activity, and restored normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance under pathological conditions. Furthermore, a moderate improvement in alveoli size and gas-exchange surface density was noted in cysteamine-treated mouse lungs in which BPD was modelled. These data indicate that TGM2 plays a role in normal lung alveolarization, and contributes to the formation of aberrant ECM structures during disordered lung alveolarization.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

et al. 2018

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“…Studies have included the examination of enzyme systems that direct the cross linking of collagen and elastin fibers, which include the lysyl oxidase, lysyl hydroxylase, and transglutaminase enzyme families. The expression of lysyl oxidases (namely Lox and LoxL1) (178), lysyl hydroxlyases (namely lysyl hydroxylase 2, also called Plod2) (369), and transglutaminase 2 (368) has been associated with BPD in clinical subjects and with arrested alveolarization in the hyperoxia-based (85% O 2 for 14 days) C57BL/6 mouse model of BPD. Studies employing pharmacological interventions or knockout mouse strains are required to causally implicate these enzyme families in aberrant lung development.…”

Section: Ecm Production and Remodelingmentioning

confidence: 99%

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

Silva

Nardiello

Pozarska

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

127

117

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Alveolarization is the process by which the alveoli, the principal gas exchange units of the lung, are formed. Along with the maturation of the pulmonary vasculature, alveolarization is the objective of late lung development. The terminal airspaces that were formed during early lung development are divided by the process of secondary septation, progressively generating an increasing number of alveoli that are of smaller size, which substantially increases the surface area over which gas exchange can take place. Disturbances to alveolarization occur in bronchopulmonary dysplasia (BPD), which can be complicated by perturbations to the pulmonary vasculature that are associated with the development of pulmonary hypertension. Disturbances to lung development may also occur in persistent pulmonary hypertension of the newborn in term newborn infants, as well as in patients with congenital diaphragmatic hernia. These disturbances can lead to the formation of lungs with fewer and larger alveoli and a dysmorphic pulmonary vasculature. Consequently, affected lungs exhibit a reduced capacity for gas exchange, with important implications for morbidity and mortality in the immediate postnatal period and respiratory health consequences that may persist into adulthood. It is the objective of this Perspectives article to update the reader about recent developments in our understanding of the molecular mechanisms of alveolarization and the pathogenesis of BPD.

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“…The transglutaminases constitute an eight-member family of calcium-dependent enzymes, which cross-link collagens and fibronectin, among other proteins ( 223 ). Of the transglutaminases, largely transglutaminase 2 (Tgm2; also called tissue transglutaminase, tTG) has been studied in lung disease and was reported to be expressed in fibroblasts, as well as epithelial, endothelial, and smooth muscle cells ( 85 , 224 ). In addition to cross-linking activity, Tgm2 is an integrin-binding adhesion co-receptor for fibronectin ( 225 ).…”

Section: Ecm Remodeling Enzymesmentioning

confidence: 99%

The Extracellular Matrix in Bronchopulmonary Dysplasia: Target and Source

Mižíková

Morty

2015

Front. Med.

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Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth that contributes significantly to morbidity and mortality in neonatal intensive care units. BPD results from life-saving interventions, such as mechanical ventilation and oxygen supplementation used to manage preterm infants with acute respiratory failure, which may be complicated by pulmonary infection. The pathogenic pathways driving BPD are not well-delineated but include disturbances to the coordinated action of gene expression, cell–cell communication, physical forces, and cell interactions with the extracellular matrix (ECM), which together guide normal lung development. Efforts to further delineate these pathways have been assisted by the use of animal models of BPD, which rely on infection, injurious mechanical ventilation, or oxygen supplementation, where histopathological features of BPD can be mimicked. Notable among these are perturbations to ECM structures, namely, the organization of the elastin and collagen networks in the developing lung. Dysregulated collagen deposition and disturbed elastin fiber organization are pathological hallmarks of clinical and experimental BPD. Strides have been made in understanding the disturbances to ECM production in the developing lung, but much still remains to be discovered about how ECM maturation and turnover are dysregulated in aberrantly developing lungs. This review aims to inform the reader about the state-of-the-art concerning the ECM in BPD, to highlight the gaps in our knowledge and current controversies, and to suggest directions for future work in this exciting and complex area of lung development (patho)biology.

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Transglutaminase 2: a new player in bronchopulmonary dysplasia?

Cited by 28 publications

References 30 publications

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

The Extracellular Matrix in Bronchopulmonary Dysplasia: Target and Source

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