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

Abstract

.) 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...

Medium throughput breathing human primary cell alveolus-on-chip model

“…Recent observations demonstrated that besides tissue stretch, the air compartment (and thus the associated surface tension) is the most important physiological stimulus for surfactant release 37 , 38 , 69 . Thus, the creation of a confluent epithelial monolayer at the air–liquid interface is a key prerequisite for tissue-specific cell differentiation on the chip.…”

“…In contrast to our earlier work, the new lung-on-chip is equipped with passive medium exchange that enables not only the reproduction of the cyclic mechanical stress, but also long-term cell culture at the air–liquid interface, and thus reproduces the unique aspects of the lung microenvironment even more closely. The details of the microenvironment have significant impacts on a wide range of biological processes, including epithelial cell polarity and cell differentiation, which in turn play important roles in determining physiological functions 32 – 38 . Furthermore, we describe a breathing lung alveolar barrier consisting of primary human alveolar epithelial and lung endothelial cells cultured in an in vivo –like environment.…”

The micromechanics of lung alveoli: structure and function of surfactant and tissue components

“…type II alveolar epithelial cells via shear forces. Hence, interfacial stress alone can result in major dysfunction of type II alveolar epithelial cells as illustrated in in vitro test systems (Hobi et al 2012 ; Ravasio et al 2011 ).…”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…A recent work employed microarray technology to demonstrate that interfacial stress leads to rapid and significant changes in the expression of genes involved in stress response and defense pathways (96). However, not only mechanical stimuli contribute to VILI pathogenesis.…”