The role of transglutaminase 2 in normal and aberrant late lung development

Abstract

A disturbed extracellular matrix (ECM) is a feature of bronchopulmonary dysplasia (BPD). How the ECM structures are malformed is not understood. Transglutaminases are ECM cross-linking enzymes, and transglutaminase 2 (Tgm2) is deregulated in experimental and clinical BPD. No role for Tgm2 in lung development has been demonstrated. We hypothesized that Tgm2 plays a role in lung alveolarization. To address this, we employed Tgm2 -/- mice in a hyperoxia-based experimental animal model of BPD. Normoxia (21% O 2 )-exposed Tgm2 -/- mice exhibited a decreased body mass (4.98 g vs. 5.51 g; P 3 vs. 0.27 cm 3 ; P =0.0022) at postnatal day (P)14.5 compared to normoxia-exposed controls. Changes in lung structure were detected comparing the two groups, suggesting an arrest in alveolarization in Tgm2 -/- mice. Total surface area (163.9 cm 2 vs. 201.7 cm 2 ; P =0.0155), septal thickness (10.36 µm vs. 8.45 µm; P =0.0142) and total alveoli number (3.253 x 10 6 vs. 4.067 x 10 6 ; P =0.0541) were perturbed in Tgm2 -/- mice. Expression levels of Tgm2 were increased by hyperoxia exposure. Total surface area (124.2 cm 2 vs. 201.7 cm 2 ; P vs. 31.73 µm; P vs. 8.45 µm; P= 0.693) and total alveoli number (1.536 x 10 6 vs. 4.067 x 10 6 ; P Tgm2 expression was upregulated by hyperoxia-expsoure in developing mouse lungs, however, genetic abrogation of Tgm2 expression was not protective. These data indicate that Tgm2 most likely plays a role in normal lung alveolarization, but does not contribute to the aberrant alveolarization seen in hyperoxia-exposed developing mouse lungs.