Pulmonary Consequences of a Deep Breath Revisited

Dietl, Paul; Frick, Manfred; Mair, Norbert; Bertocchi, Cristina; Haller, Thomas

doi:10.1159/000078176

Cited by 39 publications

(35 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1D). In vivo, a mechanical strain of the lung epithelium (occurring as a result of a deep breath, such as a yawn or a sigh or during exercise) is believed to be the major stimulus for surfactant secretion (31)(32)(33)(34); however, ATP is also present in the pulmonary hypophase, the thin liquid layer lining the alveolar epithelium (35). In particular, it is believed that mechanical strain, along with inducing a rise in [Ca 2+ ] c , leads to ATP release from ATII cells (36).…”

Section: Resultsmentioning

confidence: 99%

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Miklavc

Mair

Wittekindt

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

136

View full text Add to dashboard Cite

Ca2+ is considered a key element in multiple steps during regulated exocytosis. During the postfusion phase, an elevated cytoplasmic Ca 2+ concentration ([Ca 2+ ]) c leads to fusion pore dilation. In neurons and neuroendocrine cells, this results from activation of voltage-gated Ca 2+ channels in the plasma membrane. However, these channels are activated in the prefusion stage, and little is known about Ca 2+ entry mechanisms during the postfusion stage. This may be particularly important for slow and nonexcitable secretory cells. We recently described a "fusion-activated" Ca 2+ entry (FACE) mechanism in alveolar type II (ATII) epithelial cells. FACE follows initial fusion pore opening with a delay of 200-500 ms. The site, molecular mechanisms, and functions of this mechanism remain unknown, however. Here we show that vesicle-associated Ca 2+ channels mediate FACE. Using RT-PCR, Western blot analysis, and immunofluorescence, we demonstrate that P2X 4 receptors are expressed on exocytotic vesicles known as lamellar bodies (LBs). Electrophysiological, pharmacological, and genetic data confirm that FACE is mediated via these vesicular P2X 4 receptors. Furthermore, analysis of fluorophore diffusion into and out of individual vesicles after exocytotic fusion provides evidence that FACE regulates postfusion events of LB exocytosis via P2X 4 . Fusion pore dilation was clearly correlated with the amplitude of FACE, and content release from fused LBs was accelerated in fusions followed by FACE. Based on these findings, we propose a model for regulation of the exocytotic postfusion phase in nonexcitable cells in which Ca 2+ influx via vesicular Ca 2+ channels regulates fusion pore expansion and vesicle content release.egulated secretion is a fundamental cellular process in many different types of eukaryotic cells, with Ca 2+ -triggered exocytosis being the key element (1-4). Multiple Ca 2+ -dependent steps have been elucidated that ultimately lead to fusion of exocytic vesicles with the plasma membrane, resulting in formation of an aqueous channel, the fusion pore, through which vesicle contents are released (5-8). Although the molecular composition of the fusion pore remains elusive, there is a general acceptance that fusion pores are not merely passive structures, but that their opening and closure are highly regulated and control, or even fine-tune, vesicle content secretion (9-14). Voltage-gated Ca 2+ channels are not present (25). After LB fusion with the plasma membrane, surfactant, a water-insoluble bulky complex, largely remains entrapped within the fused vesicles (26) in which the fusion pores behave as regulated valves or mechanical barriers for release (16,27). As a result, in vitro full content release can be delayed for minutes up to hours (28).We recently reported a "fusion-activated" Ca 2+ entry (FACE) mechanism as a phenomenon in the postfusion phase of surfactant secretion (29). Given that this Ca 2+ signal occasionally spreads throughout the cell, we speculated that it might be important for triggering...

show abstract

Section: Resultsmentioning

confidence: 99%

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Miklavc

Mair

Wittekindt

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

136

View full text Add to dashboard Cite

show abstract

“…Surfactant release after a deep inspiration could also affect airway impedance, especially that of the small airways [301]. It is crucial to establish the relative importance of the various contributing factors involved in stretch-induced smooth muscle response and their relevance to asthma.…”

Section: Stretch-induced Release Of Transmitters In the Parenchyma Anmentioning

confidence: 99%

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

An¹,

Bai²,

Bates³

et al. 2007

Eur Respir J

344

298

View full text Add to dashboard Cite

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

show abstract

“…18,66,69,72). In particular, tissue stretch (ϭ tensile strain) has already been shown to be an important determinant of surfactant secretion in alveolar type II (AT II) cells (2,15,36,47,71,73). Studies on single cells revealed that stretch induces an elevation of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (23, 73), perhaps via mechanosensitive ion channels like the wellcharacterized transient receptor potential (TRP) vanilloids (reviewed in Refs.…”

mentioning

confidence: 99%

Interfacial stress affects rat alveolar type II cell signaling and gene expression

Hobi

Ravasio

Haller

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

.) showed that contact of alveolar epithelial type II cells with an air-liquid interface (I AL) leads to a paradoxical situation. It is a potential threat that can cause cell injury, but also a Ca 2ϩ -dependent stimulus for surfactant secretion. Both events can be explained by the impact of interfacial tensile forces on cellular structures. Here, the strength of this mechanical stimulus became also apparent in microarray studies by a rapid and significant change on the transcriptional level. Cells challenged with an IAL in two different ways showed activation/inactivation of cellular pathways involved in stress response and defense, and a detailed Pubmatrix search identified genes associated with several lung diseases and injuries. Altogether, they suggest a close relationship of interfacial stress sensation with current models in alveolar micromechanics. Further similarities between IAL and cell stretch were found with respect to the underlying signaling events. The source of Ca 2ϩ was extracellular, and the transmembrane Ca 2ϩ entry pathway suggests the involvement of a mechanosensitive channel. We conclude that alveolar type II cells, due to their location and morphology, are specific sensors of the IAL, but largely protected from interfacial stress by surfactant release. cell deformation; cell injury; mechanotransduction; microarray; stretch IN THE ALVEOLI, MECHANICAL forces are a constant modulator of tissue geometry and function (4). These forces arise from multiple sources, such as cyclic stretching and compression during respiration, changes in transcapillary pressure, or surface tension at the air-liquid interface (I AL ) (22). They are probably nonuniform in space and time (26,51,67) and impose either physiological responses of the cells, or pathological ones, depending on the type of tissue or the magnitude or abnormality of forces that are at work (reviewed in Refs. 18,66,69,72). In particular, tissue stretch (ϭ tensile strain) has already been shown to be an important determinant of surfactant secretion in alveolar type II (AT II) cells (2,15,36,47,71,73). Studies on single cells revealed that stretch induces an elevation of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (23, 73), perhaps via mechanosensitive ion channels like the wellcharacterized transient receptor potential (TRP) vanilloids (reviewed in Refs. 16,77). Recently, the panoply of mechanosensitive mechanisms was expanded by the finding that the I AL , the "normal" microenvironment of the AT II cells (6), may be a strong mechanical incentive as well. Two recent independent studies (55, 56) described a stimulating, but also harmful, effect of an I AL on the AT II cell function. Interestingly, interfacial contact is followed by an increase in [Ca 2ϩ ] i and release of ATP, both of which stimulate secretion (reviewed in Refs. 1, 44, 59). It has even been speculated that this response could act within a feedback loop to continuously monitor and to adjust the physical properties of the interface or the hypophase below.In addition...

show abstract

Pulmonary Consequences of a Deep Breath Revisited

Cited by 39 publications

References 37 publications

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Interfacial stress affects rat alveolar type II cell signaling and gene expression

Contact Info

Product

Resources

About

Pulmonary Consequences of a Deep Breath Revisited

Cited by 39 publications

References 37 publications

Fusion-activated Ca 2+ entry via vesicular P2X 4 receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Fusion-activated Ca 2+ entry via vesicular P2X 4 receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Interfacial stress affects rat alveolar type II cell signaling and gene expression

Contact Info

Product

Resources

About

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes

Fusion-activated Ca ²⁺ entry via vesicular P2X ₄ receptors promotes fusion pore opening and exocytotic content release in pneumocytes