Mechanical stretch-induced serotonin release from pulmonary neuroendocrine cells: implications for lung development

Abstract

(serotonin, and peptides (e.g., bombesin, calcitonin) with growth factor-like properties and are thought to play an important role in lung development. Because physical forces are essential for lung growth and development, we investigated the effects of mechanical strain on 5-HT release in PNEC freshly isolated from rabbit fetal lung and in the PNEC-related tumor H727 cell line. Cultures exposed to sinusoidal cyclic stretch showed a significant 5-HT release inhibitable with gadolinium chloride (10 nM), a blocker of mechanosensitive channels. In contrast to hypoxia (PO 2 ϳ 20 mmHg), stretch-induced 5-HT release was not affected by Ca 2ϩ -free medium or nifedipine (50 M), excluding the exocytic pathway. In H727 cells, stretch failed to release calcitonin, a peptide stored within dense core vesicles (DCV), whereas hypoxia caused massive calcitonin release. 5-HT released by mechanical stretch is derived predominantly from the cytoplasmic pool, because it is rapid (ϳ5 min) and is releasable from early (20 days of gestation) fetal PNEC containing few DCV. Both mechanical stretch and hypoxia upregulated expression of tryptophan hydroxylase, the rate-limiting enzyme of 5-HT synthesis. We conclude that mechanical strain is an important physiological stimulus for the release of 5-HT from PNEC via mechanosensitive channels with potential effects on lung development and resorption of lung fluid at the time of birth. mechanosensitive ion channels; amine storage pools; neuroendocrine cell secretion; hypoxia-induced secretion; fetal lung fluid THE SYSTEM OF PULMONARY NEUROENDOCRINE CELLS (PNEC) is composed of amine (serotonin, 5-HT)-and peptide (e.g., bombesin, calcitonin)-producing cells widely distributed within the airway mucosa of human and animal lungs (13,34,40). PNEC occur as single cells and as distinctive innervated clusters, neuroepithelial bodies (NEB). Whereas solitary PNEC populate the mucosa of the trachea and bronchi up to the terminal bronchioles, NEB are found only within intrapulmonary airways, where they appear concentrated at airway branch points (7). Pulmonary NEB function as airway O 2 sensors, because they express a membrane-bound O 2 -sensing molecular complex composed of an O 2 -sensitive K ϩ channel coupled to an O 2 -sensing protein, NADPH oxidase (9, 10, 45). Hypoxia activates the O 2 sensor, leading to Ca 2ϩ -dependent exocytosis of dense core vesicles (DCV), the storage site of amine and peptides, and the release of these mediators acting locally or via vagal afferents (9, 10). Hypoxia induced 5-HT release from NEB cells is dose dependent and occurs within the physiological range expected in the airway (PO 2 ϳ 95 mmHg) (17). The precise role of solitary PNEC and whether they are functionally distinct from NEB is not known, although they share identical neuroendocrine and molecular markers as well as innervation (13,34,40). PNEC/NEB appear prominent in fetal and neonatal lungs but are less conspicuous in the lungs of adults because of a "dilutional" effect of postnatal lung growth (20).PNEC are th...

Effect of Tryptophan Hydroxylase 1 Deficiency on the Development of Hypoxia-Induced Pulmonary Hypertension

“…3,4,17,18 Tph1 is expressed in lung pulmonary neuroendocrine cells, and both hypoxia and mechanical stretch have been shown to induce increased Tph1 expression and serotonin release in rabbit lung. 19 In light of these observations, our results suggest that, in mice, chronic hypoxia itself may induce Tph1 synthesis and subsequent serotonin release, which acts as a mitogen in pulmonary arteries, contributing to the pulmonary vascular remodeling and subsequent onset of pulmonary hypertension. The elevation of pulmonary vascular tone that accompanies PAH is likely to induce further stretch-induced Tph1 expression and serotonin release.…”

“…Hypoxia and mechanical stretch have been shown increase Tph1 expression and serotonin release in rabbit lung. 19 Hence, hypoxia may induce Tph1, which results in an elevation of peripheral serotonin, which contributes to hypoxia-induced PAH. The resulting increased pulmonary pressure and vessel tension may then lead to further Tph1 expression and serotonin release.…”

Bronchopulmonary neuroendocrine tumors

“…Serotonin and other peptides (eg, bombesin, calcitonin) with growth factor-like properties are thought to play an important role in normal lung development. 18 PNECs are most noticeably present in the perinatal period, particularly in species that are relatively immature at birth such as humans and, in addition to their role in lung development, may have a crucial contribution in adaptation to air breathing at birth. 19 NEBs are considered to serve as airway chemoreceptor cells responsive to hypoxia and are thought to activate vagal afferents, thereby participating in the regulation of breathing.…”

Serotonin Decreases Alveolar Epithelial Fluid Transport via a Direct Inhibition of the Epithelial Sodium Channel

“…Alveolar type II cells also have a tryptophan hydroxylase activity that suggests their ability to produce 5-HT from the amino acid, tryptophan (40). Recent publications have shown that 5-HT can be released in the respiratory system by the neuroendocrine epithelial cells after exposure to hypoxia or epithelial stretch (10,11), two common conditions found in patients with ALI. Hypoxia is known to cause an inhibition of ion transport across the distal lung epithelium (4).…”

“…Its role in the pathophysiology of asthma and pulmonary hypertension is well established (7)(8)(9). The lung neuroendocrine system, represented by pulmonary neuroepithelial cells in upper airway and neuroepithelial bodies in distal airway (including alveoli), is able to secrete 5-HT into the airspace under various stimuli, such as hypoxia and epithelial stretch (10,11), two conditions commonly observed in patients with ALI. Therefore, under these conditions, locally secreted 5-HT could modulate the function of epithelial ion channels, including ENaC, and affect its function.…”