Thyroid transcription factor-1 (TTF-1) deficiency syndrome is characterized by neurologic, thyroidal, and pulmonary dysfunction. Children usually have mild-to-severe respiratory symptoms and occasionally die of respiratory failure. Herein, we describe an infant with a constitutional 14q12-21.3 haploid deletion encompassing the TTF-1 gene locus who had cerebral dysgenesis, thyroidal dysfunction, and respiratory insufficiency. The clinical course was notable for mild hyaline membrane disease, continuous ventilatory support, and symmetrically distributed pulmonary cysts by imaging. He developed pneumonia and respiratory failure and died at 8 months. Pathologically, the lungs had grossly visible emphysematous changes with ''cysts'' up to 2 mm in diameter. The airway generations and radial alveolar count were diminished. In addition to acute bacterial pneumonia, there was focally alveolar septal fibrosis, pneumocyte hypertrophy, and clusters of airspace macrophages. Ultrastructurally, type II pneumocytes had numerous lamellar bodies, and alveolar spaces contained fragments of type II pneumocytes and extruded lamellar bodies. Although immunoreactivity for surfactant protein SP-A and ABCA3 was diminished, that for SP-B and proSP-C was robust, although irregularly distributed, corresponding to the distribution of type II pneumocytes. Immunoreactivity for TTF-1 protein was readily detected. In summation, we document abnormal airway and alveolar morphogenesis and altered expression of surfactant-associated proteins, which may explain the respiratory difficulties encountered in TTF-1 haploinsufficiency. These findings are consistent with experimental evidence documenting the important role of TTF-1 in pulmonary morphogenesis and surfactant metabolism.Keywords: alveolar growth abnormality; cerebral dysgenesis; thyroid transcription factor-1; bronchopulmonary dysplasia; surfactant protein Thyroid transcription factor-1 (TTF-1, also known as TITF-1, NKX2-1, or TEBP), a member of the NKx2 homeodomain transcription factor family, is essential for the morphogenesis of thyroid, lungs, and brain (3).TTF-1 knockout mice fail to develop these organs and die at birth, whereas the heterozygous mice reach term (4).TTF-1 haploinsufficiency in humans is responsible for a rare syndrome (TTF-1 deficiency syndrome) characterized by neurological, thyroidal, and pulmonary dysfunction (5-9). In a recent series that also reviewed the clinical and pathologic findings of 46 patients with TTF-1 deficiency, pulmonary disease occurred in 54%, with ''infant respiratory distress syndrome'' being the most common (7). The pulmonary pathology has been described briefly in one patient, whereas only one other case report illustrates the pathologic findings (10, 11).We identified an infant with cerebral dysgenesis, thyroidal dysfunction, respiratory insufficiency, and a karyotype showing a 14q13-21.3 deletion encompassing the TTF-1 gene locus. The infant died at 8 months with pneumonia and respiratory insufficiency. We describe his pulmonary pathology, incl...

Lakser, Oren J., Robert P. Lindeman, and Jeffrey J. Fredberg. Inhibition of the p38 MAP kinase pathway destabilizes smooth muscle length during physiological loading. Am J Physiol Lung Cell Mol Physiol 282: L1117-L1121, 2002 10.1152/ajplung.00230.2000.-We tested the hypothesis that mechanical plasticity of airway smooth muscle may be mediated in part by the p38 mitogen-activated protein (MAP) kinase pathway. Bovine tracheal smooth muscle (TSM) strips were mounted in a muscle bath and set to their optimal length, where the active force was maximal (Fo). Each strip was then contracted isotonically (at 0.32 Fo) with ACh (maintained at 10 Ϫ4 M) and allowed to shorten for 180 min, by which time shortening was completed and the static equilibrium length was established. To simulate the action of breathing, we then superimposed on this steady distending force a sinusoidal force fluctuation with zero mean, at a frequency of 0.2 Hz, and measured incremental changes in muscle length. We found that TSM strips incubated in 10 M SB-203580-HCl, an inhibitor of the p38 MAP kinase pathway, demonstrated a greater degree of fluctuation-driven lengthening than did control strips, and upon removal of the force fluctuations they remained at a greater length. We also found that the force fluctuations themselves activated the p38 MAP kinase pathway. These findings are consistent with the hypothesis that inhibition of the p38 MAP kinase pathway destabilizes muscle length during physiological loading. mitogen-activated protein; contraction; plasticity; perturbed myosin binding ASTHMA IS CHARACTERIZED by reversible airway obstruction, airway inflammation, and airway hyperresponsiveness to nonspecific agonists. The end result is excessive airway narrowing. Airway narrowing is driven by the action of airway smooth muscle and its actomyosin contractile machinery, but myosin exerts its mechanical effects within a cytoskeletal scaffolding that is extensible and in a continuous state of remodeling (6,8,21,23,24).In this connection, load fluctuations are imposed continuously on airway smooth muscle by the tidal action of breathing. These fluctuations are known to inhibit the development of active force and stiffness (7,9,22,27) and result in smooth muscle lengthening (4). Although the direct effects of tidal stretch on actomyosin bridge dynamics can explain much of the force and stiffness inhibition (4), it is thought that important changes in the cytoskeleton are also induced by changes of the muscle load in time (8, 21).Here we have investigated the hypothesis that activation of p38 mitogen-activated protein (MAP) kinase may modulate muscle mechanical responses to imposed load fluctuations during contractile stimulation. We show that the p38 MAP kinase inhibitor SB-203580-HCl increased the degree of smooth muscle lengthening induced by load fluctuations. As such, these data suggest that activation of p38 MAP kinase stabilizes airway smooth muscle subjected to dynamic loading conditions that approximate those that prevail in vivo. Moreover, t...

Organogenesis is orchestrated by cell and tissue interactions mediated by molecular signals. Identification of relevant signals, and the tissues that generate and receive them, are important goals of developmental research. Here, we demonstrate that Retinoic Acid (RA) is a critical signaling molecule important for morphogenesis of mammalian submandibular salivary glands (SMG). By examining late stage RA deficient embryos of Rdh10 mutant mice we show that SMG development requires RA in a dose-dependent manner. Additionally, we find that active RA signaling occurs in SMG tissues, arising earlier than any other known marker of SMG development and persisting throughout gland morphogenesis. At the initial bud stage of development, we find RA production occurs in SMG mesenchyme, while RA signaling occurs in epithelium. We also demonstrate active RA signaling occurs in glands cultured ex vivo, and treatment with an inhibitor of RA signaling blocks growth and branching. Together these data identify RA signaling as a direct regulator of SMG organogenesis.