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1 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
4 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: ernest.cutz{at}sickkids.ca.
Pulmonary Neuroendocrine cells (PNEC) produce amine (serotonin, 5HT) and peptides (e.g. bombesin, calcitonin) with growth factor like properties and are thought to play an important role in lung development. Since physical forces are essential for lung growth and development we investigated the effects of mechanical strain on 5HT 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 5HT release inhibitable with gadolinium chloride (10nM) a blocker of mechanosensitive channels .In contrast to hypoxia (pO2 ~ 20mmHg), stretch induced 5HT release was not affected by Ca2+ free medium or nifedipine (50µM), excluding the exocytic pathway. In H727 cells, stretch failed to release calcitonin, a peptide stored within dense corevesicles (DCV), while hypoxia caused massive calcitonin release. 5HT released by mechanical stretch is derived predominantly from the cytoplasmic pool since it is rapid (~5 min) and is releasable from early (E20) fetal PNEC containing few DCV. Both mechanical stretch and hypoxia up regulated expression of tryptophan hydroxylase, the rate limiting enzyme of 5HT synthesis. We conclude that mechanical strain is an important physiologic 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.
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