Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation

Abstract

Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter embryonic lung airway branching and temporal-spatial differentiation of the lung epithelium and mesenchyme. Gestational day 11.5 embryonic mouse lungs were cultured for 72 h in BGJb serum-free medium without or with added T 3 (0.2, 2.0, 10.0, or 100 nM). Evaluation of terminal bud counts showed a dose-and time-dependent decrease in branching morphogenesis. Cell proliferation was also significantly decreased with higher doses of T 3. Morphometric analysis of lung histology showed that T 3 caused a dose-dependent decrease in mesenchyme and increase in cuboidal epithelia and airway space. Immunocytochemistry showed that with T 3 treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development. We conclude that exogenous T 3 treatment during early lung development accelerated epithelial and mesenchymal cell differentiation at the expense of premature reduction in new branch formation and lung growth. triiodothyronine; lung development; Nkx2.1; Hoxb5; surfactant protein-C DURING FETAL DEVELOPMENT, lung morphology and differentiation of the airway lining epithelium change with advancing gestation. In the mouse, lung morphogenesis starts at gestational day 9.5 (Gd 9.5) with the evagination of the lung primordium from the ventral foregut to form the prospective trachea and two lung buds followed by the dichotomous branching of each lung bud through the process of branching morphogenesis. Differentiation of this lung primordium into the bronchial and pulmonary acinar systems begins during this period. The restriction of cell types and in some cases loss of cell-specific markers herald changes in the stage of bronchiolar versus distal epithelial cell fate and differentiation (48,58). These processes of airway branching and cytodifferentiation require a close interaction between endodermal epithelium and adjacent mesenchyme and are affected by specific factors and hormonal systems active in the developing embryo and fetus (1,22,24,35,38). In particular, in rodent lung organ cultures and human lung explant cultures, triiodothyronine (T 3 ), the active form of thyroid hormone, influences late fetal lung development by accelerating epithelial cell differentiation leading to surfactant phospholipid synthesis and by regulating lung structural development and alveolar septation (9,11,26,38). Little is known about the cellular expression pattern of T 3 receptors during fetal lung development, but they are present in rodent and human lung tissue during the pseudoglandular period and increase in quantity and binding affinity as lung development progresses (6,13,18,20,23). Although there are relatively low levels of T 3 and its receptors in early fetal life, maternal hypo-or hyperthyroidism le...

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“…In the mouse and rat, thyroid hormone affects lung epithelial and mesenchymal differentiation, lung branching morphogenesis, and postnatal alveolar maturation (Archavachotikul et al, 2002;Massaro et al, 1986;Volpe et al, 2003). However, Tpst2−/− mice have normal postnatal viability (Borghei et al, 2006) and their lungs are histological normal at P1 and beyond (data not shown) despite the presence of severe hypothyroidism.…”

The role of oxygen tension in the regulation of embryonic lung development

“…1. The lungs exhibited the normal progression of monochotomous and dichotomous airway branching in both groups [11,12]. The lungs of the hypoxic group had similar branching pattern with the normoxic group.…”

Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support

“…In fact, several groups have discovered that triiodothyronine stimulates epithelial differentiation and regulates lung structural maturity and alveolar septation. 7 Similarly, Morishige and Joun 11 showed, by inducing hypothyroidism in rat pups, that thyroid hormone was necessary during lung maturation, although only through optimization of glucocorticoid actions. Interestingly, serum thyroglobulin, levels of which are elevated in hyperthyroidism, inhibits the expression of thyroid transcription factor-1 (TTF-1), a necessary factor for normal lung epithelial differentiation and tissue organization.…”

“…Knowledge of the presence and activity of nuclear thyroid hormone receptors has proven useful. The concentrations of thyroid hormone receptors in fetal lung tissue have been shown to increase during gestation, 7,8 whereas the majority of thyroid hormone receptors are found within alveolar type II cells among adults. 9,10 The presence and relative concentrations of thyroid hormone receptors during fetal life suggest an important role for thyroid hormone in pulmonary differentiation and function.…”