Protein Cross-linking Mediated by Tissue Transglutaminase Correlates with the Maturation of Extracellular Matrices During Lung Development

Abstract

At birth, the mammalian lung is still immature. The alveoli are not yet formed and the interairspace walls contain two capillary layers which are separated by an interstitial core. After alveolarization (first 2 postnatal weeks in rats) the alveolar septa mature: their capillary layers merge, the amount of connective tissue decreases, and the mature lung parenchyma is formed (second and third week). During the first 3 wk of life the role of tissue transglutaminase (tTG) was studied in rat lung by immunostaining of cryostat and paraffin sections, by Northern and Western blotting, and by a quantitative determination of gamma-glutamyl-epsilon-lysine. While enzyme activity and intracellular tTG were already present before term, the enzyme product (gamma-glutamyl-epsilon-lysine-crosslink) and extracellular tTG appeared between postnatal days 10 and 19 in the lung parenchyma. In large blood vessels and large airways, which mature earlier than the parenchyma, both the enzyme product and extracellular tTG had already appeared at the end of the first postnatal week. We conclude that tTG is expressed and externalized into the extracellular matrix of lung shortly before maturation of an organ area. Because tTG covalently and irreversibly crosslinks extracellular matrix proteins, we hypothesize that it may prevent or delay further remodeling of basement membranes and may stabilize other extracellular components, such as microfibrils.

The modulus of elasticity of fibrillin-containing elastic fibres in the mesoglea of the hydromedusaPolyorchis penicillatus

“…Reber-Müller et al (1995, 1996) suggested this possibility, although Schmid et al (1999) suggested that the microfibrils alone were responsible for the observed elasticity of the fibres. It seems more likely that the functionally continuous model is correct, particularly given the high volume fraction and high degree of overlap of the microfibrils in the fibre and observations by several authors of irreversible transglutaminase-derived crosslinks between fibrillin-rich microfibrils in several systems (Thurmond and Trotter, 1996;Qian and Granville, 1997;Schittny et al, 1997;Kielty et al, 2002). In either case, however, we conclude that the modulus of the microfibrils must be much less than the 78-96·MPa reported by Sherratt et al (2003) and that it should be of the order of 1·MPa.…”

Molecular Basis of Elastic Fiber Formation

“…Transglutaminases catalyze the formation of an isopeptide ␥-glutamyl-⑀-lysine bond either between or within polypeptide chains. Tissue transglutaminase (tTG, TG-2, TG C ) is important in stabilizing developing extracellular matrices including lung and bone and in wound repair (30,31). The cross-link site on fibrillin-1 was localized to three glutamines within the fibrillin-1 TB2 domain (exon 17), which are on the domain surface.…”

High resolution tomographic imaging of the alveolar region of the mammalian lung

“…The first two components have been previously described in detail elsewhere [61,62,84,85] and thus are only recapitulated briefly here. The em-phasis of the present work is on the third component; the experimental methods are described in detail below.…”