Lamellar Body Exocytosis by Cell Stretch or Purinergic Stimulation: Possible Physiological Roles, Messengers and Mechanisms

Dietl, Paul; Liss, Birgit; Felder, Edward; Miklavc, Pika; Wirtz, Hubert

doi:10.1159/000272046

Cited by 34 publications

(31 citation statements)

References 137 publications

(164 reference statements)

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“…Rotenone is known to inhibit mitochondrial transmembrane potential (ΔΨ) and thus ATP production. ATP induces surfactant secretion binding to purinergic receptors 28. However, in our experiments, this mechanism does not play a relevant role because LB secretion was enhanced and not inhibited after rotenone application.…”

Section: Discussioncontrasting

confidence: 66%

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

Kiefmann

Tank

Tritt

et al. 2019

Thorax

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BackgroundIn acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), leading to a decline of the alveolar CO2 concentration [CO2]iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far.MethodsIn isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+]cyt or [Ca2+]mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3–7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot.ResultsLow [CO2]iA decreased [Ca2+]cyt and increased [Ca2+]mito in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses.ConclusionsAccordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+]cyt reduces surfactant secretion and thus regional ventilation in lung regions with high VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.

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Section: Discussioncontrasting

confidence: 66%

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

Kiefmann

Tank

Tritt

et al. 2019

Thorax

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“…Within the alveolar lining fluid, ATP might reach millimolar concentrations (58), but the source of it is essentially unknown. Beside a supposed release from scattered purinergic nerve terminals, and release due to cell membrane stress failures, a channel-gated release from AT II cells, as well as a mechanosensitive ATP-exocytosis, has been proposed (16,55). Here, a release of ATP, in concentrations similar to those reported by Patel et al (49) for cyclic stretch, was detected after a brief I AL exposure (ϳ10 s).…”

Section: Discussionmentioning

confidence: 59%

“…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.…”

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

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.) 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...

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“…LBs fuse with the plasma membrane in a sequential fashion for up to 20 min after stimulation (23 (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).…”

Section: Camentioning

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.

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136

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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...

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Lamellar Body Exocytosis by Cell Stretch or Purinergic Stimulation: Possible Physiological Roles, Messengers and Mechanisms

Cited by 34 publications

References 137 publications

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

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

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

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Lamellar Body Exocytosis by Cell Stretch or Purinergic Stimulation: Possible Physiological Roles, Messengers and Mechanisms

Cited by 34 publications

References 137 publications

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function

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

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

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