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FEBS J. 2018 Jun 23. doi: 10.1111/febs.14596. [Epub ahead of print]

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

Author information

1
Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Giessen, Germany, Bad Nauheim, Germany.
2
Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Germany.
3
Institute of Virology and Cell Biology, University of Lübeck, Germany.
4
Graduate School of Pharmaceutical Sciences, Nagoya University, Japan.
5
Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UK.
6
Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
7
Department of Dermatology, University of Lübeck, Germany.

Abstract

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 Nε -(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.

KEYWORDS:

alveolarization; bronchopulmonary dysplasia; cysteamine; extracellular matrix; transglutaminase

PMID:
29935061
DOI:
10.1111/febs.14596

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