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

2006 ◽  
Vol 290 (1) ◽  
pp. L185-L193 ◽  
Author(s):  
Jie Pan ◽  
Ian Copland ◽  
Martin Post ◽  
Herman Yeger ◽  
Ernest Cutz
Keyword(s):  
Lung Development ◽  
Tryptophan Hydroxylase ◽  
Mechanical Strain ◽  
Fetal Lung ◽  
Mechanical Stretch ◽  
Serotonin Release ◽  
Neuroendocrine Cells ◽  
Cyclic Stretch ◽  
Mechanosensitive Channels ◽  
Pulmonary Neuroendocrine Cells

Pulmonary neuroendocrine cells (PNEC) produce amine (serotonin, 5-HT) 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 (Po2 ∼ 20 mmHg), stretch-induced 5-HT release was not affected by Ca2+-free medium or nifedipine (50 μM), 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 (∼5 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.

scholarly journals Amniotic fluid stem cell extracellular vesicles promote fetal lung branching and cell differentiation in experimental congenital diaphragmatic hernia

2022 ◽  
Author(s):  
Kasra Khalaj ◽  
Rebeca Lopes Figueira ◽  
Lina Antounians ◽  
Sree Gandhi ◽  
Matthew Wales ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Congenital Diaphragmatic Hernia ◽  
Extracellular Vesicles ◽  
Diaphragmatic Hernia ◽  
Lung Development ◽  
Pulmonary Hypoplasia ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Neuroendocrine Cells ◽  
Beta Catenin

Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by impaired branching morphogenesis and differentiation. We have previously demonstrated that administration of extracellular vesicles derived from rat amniotic fluid stem cells (AFSC-EVs) rescues development of hypoplastic lungs at the pseudoglandular and alveolar stages in rodent models of CDH. Herein, we tested whether AFSC-EVs exert their regenerative effects at the canalicular and saccular stages, as these are translationally relevant for clinical intervention. To induce fetal pulmonary hypoplasia, we gavaged rat dams with nitrofen at embryonic day 9.5 and demonstrated that nitrofen-exposed lungs had impaired branching morphogenesis, dysregulated signaling pathways relevant to lung development (FGF10/FGFR2, ROBO/SLIT, Ephrin, Neuropilin 1, beta-catenin) and impaired epithelial and mesenchymal cell marker expression at both stages. AFSC-EVs administered to nitrofen-exposed lung explants rescued airspace density and increased the expression levels of key factors responsible for branching morphogenesis. Moreover, AFSC-EVs rescued the expression of alveolar type 1 and 2 cell markers at both canalicular and saccular stages, and restored markers of club, ciliated epithelial, and pulmonary neuroendocrine cells at the saccular stage. AFSC-EV treated lungs also had restored markers of lipofibroblasts and PDGFRA+ cells to control levels at both stages. EV tracking showed uptake of AFSC-EV RNA cargo throughout the fetal lung and an mRNA-miRNA network analysis identified that several miRNAs responsible for regulating lung development processes were contained in the AFSC-EV cargo. These findings suggest that AFSC-EV based therapies hold potential for restoring fetal lung growth and maturation in babies with pulmonary hypoplasia secondary to CDH.

Interleukin-10 protects cultured fetal rat type II epithelial cells from injury induced by mechanical stretch

2008 ◽  
Vol 294 (2) ◽  
pp. L225-L232 ◽  
Author(s):  
Hyeon-Soo Lee ◽  
Yulian Wang ◽  
Benjamin S. Maciejewski ◽  
Kenny Esho ◽  
Christiaan Fulton ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Lung Development ◽  
Mechanical Stretch ◽  
Interleukin 10 ◽  
Cyclic Stretch ◽  
Mechanical Forces ◽  
Type Ii ◽  
Fetal Rat ◽  
The Media

Mechanical ventilation plays a central role in the pathogenesis of bronchopulmonary dysplasia. However, the mechanisms by which excessive stretch of fetal or neonatal type II epithelial cells contributes to lung injury are not well defined. In these investigations, isolated embryonic day 19 fetal rat type II epithelial cells were cultured on substrates coated with fibronectin and exposed to 5% or 20% cyclic stretch to simulate mechanical forces during lung development or lung injury, respectively. Twenty percent stretch of fetal type II epithelial cells increased necrosis, apoptosis, and proliferation compared with control, unstretched samples. By ELISA and real-time PCR (qRT-PCR), 20% stretch increased secretion of IL-8 into the media and IL-8 gene expression and inhibited IL-10 release. Interestingly, administration of recombinant IL-10 before 20% stretch did not affect cell lysis but significantly reduced apoptosis and IL-8 release compared with stretched samples without IL-10. Collectively, our studies suggest that IL-10 may play an important role in protection of fetal type II epithelial cells from injury secondary to stretch.

scholarly journals A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells

2010 ◽  
Vol 298 (6) ◽  
pp. L775-L783 ◽  
Author(s):  
Yulian Wang ◽  
Benjamin S. Maciejewski ◽  
Diana Drouillard ◽  
Melissa Santos ◽  
Michael A. Hokenson ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Lung Development ◽  
Fetal Lung ◽  
Mechanical Stretch ◽  
Erk Pathway ◽  
Type Ii ◽  
Caveolin 1 ◽  
Fetal Lung Development ◽  
Type Ii Cell

Mechanical forces are critical for fetal lung development. Using surfactant protein C (SP-C) as a marker, we previously showed that stretch-induced fetal type II cell differentiation is mediated via the ERK pathway. Caveolin-1, a major component of the plasma membrane microdomains, is important as a signaling protein in blood vessels exposed to shear stress. Its potential role in mechanotransduction during fetal lung development is unknown. Caveolin-1 is a marker of type I epithelial cell phenotype. In this study, using immunocytochemistry, Western blotting, and immunogold electron microscopy, we first demonstrated the presence of caveolin-1 in embryonic day 19 (E19) rat fetal type II epithelial cells. By detergent-free purification of lipid raft-rich membrane fractions and fluorescence immunocytochemistry, we found that mechanical stretch translocates caveolin-1 from the plasma membrane to the cytoplasm. Disruption of the lipid rafts with cholesterol-chelating agents further increased stretch-induced ERK activation and SP-C gene expression compared with stretch samples without disruptors. Similar results were obtained when caveolin-1 gene was knocked down by small interference RNA. In contrast, adenovirus overexpression of the wild-type caveolin-1 or delivery of caveolin-1 scaffolding domain peptide inside the cells decreased stretch-induced ERK phosphorylation and SP-C mRNA expression. In conclusion, our data suggest that caveolin-1 is present in E19 fetal type II epithelial cells. Caveolin-1 is translocated from the plasma membrane to the cytoplasm by mechanical stretch and functions as an inhibitory protein in stretch-induced type II cell differentiation via the ERK pathway.

scholarly journals Mechanotransduction by GEF-H1 as a novel mechanism of ventilator-induced vascular endothelial permeability

2010 ◽  
Vol 298 (6) ◽  
pp. L837-L848 ◽  
Author(s):  
Anna A. Birukova ◽  
Panfeng Fu ◽  
Junjie Xing ◽  
Bakhtiyor Yakubov ◽  
Ivan Cokic ◽  
...  
Keyword(s):  
Mechanical Strain ◽  
Lung Ventilation ◽  
Mechanical Stretch ◽  
Fiber Formation ◽  
Cyclic Stretch ◽  
Vascular Endothelial ◽  
Nucleotide Exchange ◽  
Barrier Dysfunction ◽  
Network Cell

Pathological lung overdistention associated with mechanical ventilation at high tidal volumes (ventilator-induced lung injury; VILI) compromises endothelial cell (EC) barrier leading to development of pulmonary edema and increased morbidity and mortality. We have previously shown involvement of microtubule (MT)-associated Rho-specific guanine nucleotide exchange factor GEF-H1 in the agonist-induced regulation of EC permeability. Using an in vitro model of human pulmonary EC exposed to VILI-relevant magnitude of cyclic stretch (18% CS) we tested a hypothesis that CS-induced alterations in MT dynamics contribute to the activation of Rho-dependent signaling via GEF-H1 and mediate early EC response to pathological mechanical stretch. Acute CS (30 min) induced disassembly of MT network, cell reorientation, and activation of Rho pathway, which was prevented by MT stabilizer taxol. siRNA-based GEF-H1 knockdown suppressed CS-induced disassembly of MT network, abolished Rho signaling, and attenuated CS-induced stress fiber formation and EC realignment compared with nonspecific RNA controls. Depletion of GEF-H1 in the murine two-hit model of VILI attenuated vascular leak induced by lung ventilation at high tidal volume and thrombin-derived peptide TRAP6. These data show for the first time the critical involvement of microtubules and microtubule-associated GEF-H1 in lung vascular endothelial barrier dysfunction induced by pathological mechanical strain.

Mesenchymal determination of mechanical strain-induced fetal lung cell proliferation

1998 ◽  
Vol 275 (3) ◽  
pp. L545-L550 ◽  
Author(s):  
Jing Xu ◽  
Mingyao Liu ◽  
A. Keith Tanswell ◽  
Martin Post
Keyword(s):  
Epithelial Cells ◽  
Dna Synthesis ◽  
Lung Development ◽  
Mechanical Strain ◽  
Fetal Lung ◽  
Cell Types ◽  
Fetal Lung Development ◽  
Fetal Rat ◽  
Fetal Rat Lung ◽  
Fetal Breathing Movements

Fetal breathing movements play an important role in normal fetal lung growth. We have previously shown that an intermittent mechanical strain regimen (60 cycles/min, 15 min/h), simulating normal fetal breathing movements, stimulated growth of mixed fetal rat lung cells in organotypic culture. In the present study, we examined the individual responses of the two major fetal lung cell types, fibroblasts and epithelial cells, to mechanical strain. Also, we investigated the effect of mesenchymal-epithelial interactions on strain-induced cell proliferation during fetal lung development. Fibroblasts and epithelial cells from day 18to day 21 fetal rat lung (term = 22 days), cultured alone or as various recombinants, were subjected to either a 48-h static culture or to strain, and DNA synthesis was measured. Both cell types responded individually to strain with enhanced DNA synthesis throughout late fetal lung development. Independent of the recombination ratio, there was no additive response to strain when fibroblasts and epithelial cells from the same gestation were recombined. In contrast, strain-induced DNA synthesis was suppressed when cells from different gestations were recombined. The ontogenic response pattern of recombinants to mechanical strain was similar to that of fibroblasts but not of epithelial cells. Strain-induced proliferation increased and peaked at the early canalicular stage of lung development at 19 days of gestation and declined thereafter. We conclude that strain-enhanced growth of the fetal lung is gestation dependent and that the gestational response to mechanical force is regulated by the mesenchyme.

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