Brigham C. Willis

Endothelin-1 (ET-1) is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial–mesenchymal transition (EMT), which was recently demonstrated in alveolar epithelial cells (AEC), may play an important role in the pathogenesis of IPF and other forms of pulmonary fibrosis. Whether ET-1 contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of ET-1 and to determine if ET-1 induces EMT in AEC. We demonstrate that ET-1 is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors (ET-A) and, to a lesser extent, type B receptors (ET-B), suggesting autocrine or paracrine function for alveolar ET-1. In addition, ET-1 induces EMT through ET-A activation. Furthermore, TGF-β1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1–induced EMT is attenuated by a TGF-β1–neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A–mediated TGF-β1 production. These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial–mediated lung diseases.

To compare the pressure-rate products and phase angles of children during minimal support ventilation and after extubation. Prospective, randomized single-center trial in a pediatric intensive care unit in a tertiary children’s hospital. Seventeen endotracheally intubated, mechanically ventilated children were placed on T-piece, T-piece with heliox, continuous positive airway pressure, and pressure support in random order. Esophageal pressure swings, phase angles, respiratory mechanics, and physiological parameters were measured on these modes and after extubation. Pressure-rate product postextubation was significantly higher than on support modes. For each mode and after extubation they were: pressure support 198±31, continuous positive airway pressure 237±30, T-piece 323±47, T-piece/heliox 308±61, and extubation 378±43 cmH₂O/min. Phase angles were significantly higher during T-piece ventilation than pressure support but not did not differ significantly from postextubation. Assessment of effort of breathing during even minimal mechanical ventilation may underestimate postextubation effort in children. Postextubation pressure-rate product and hence “effort of breathing” in children is best approximated by T-piece ventilation.