Review
Stretch stimulation: its effects on alveolar type II cell function in the lung

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Abstract

Mechanical stimuli regulate cell function in much the same way as chemical signals do. This has been studied in various cell types, particularly those with defined mechanical roles. The alveolar type II cell (ATII) cell, which is part of the alveolar epithelium of the lung, is responsible for the synthesis and secretion of pulmonary surfactant. It is now widely believed that stretch of ATII cells, which occurs during breathing, is the predominant physiological trigger for surfactant release. To study this, investigators have used an increasingly sophisticated array of in vitro and in vivo models. Using various stretch devices and models of lung ventilation and expansion, it has been shown that stretch regulates multiple activities in ATII cells. In addition to surfactant secretion, stretch triggers the differentiation of ATII to alveolar type I cells, as well as ATII cell apoptosis. In doing so, stretch modulates the proportion of these cells in the lung epithelium during both development and maturation of the lung and following lung injury. From such studies, it appears that mechanical distortion plays an integral part in maintaining the overall structure and function of the lung.

Introduction

Over the past few years there has been increasing interest in mechanical stimulation and its role in the regulation of cell function. Cell proliferation, differentiation, secretion, movement, signal transduction and gene expression are all events that are modified by physiologically relevant mechanical forces. These include static, incremental and cyclic stretch, as well as twisting, compression, osmotic pressure, and shear stresses (Banes et al., 1995).

Although most cells are subjected to some form of mechanical force, the majority of studies have focused on differentiated cells with defined mechanical roles. These include skeletal, skin and muscle cells, as well as various cell types associated with the vascular system. The lung is another organ in the body subjected to a range of mechanical forces. Blood flow, respiratory distortion of the alveoli and changes in surface tension at the air–liquid interface within the alveoli all occur during breathing, influencing lung development as well as the structure and functional capacity of the mature lung. The role of such mechanical influences in the lung has gained particular clinical importance over the last few decades. This is due, in part, to the widespread use of mechanical ventilation in the treatment of respiratory disorders and the inherent possibility that certain ventilation regimens could in fact exacerbate existing lung damage.

The lung epithelium is composed of two cell types: the alveolar type I (ATI) gas exchange cell and the alveolar type II (ATII) cell in which pulmonary surfactant is synthesized and stored. Surfactant, which regulates gas exchange by modulating surface tension within the alveolar compartment, is secreted from ATII cells in response to a range of well-studied secretagogues, including ATP, and circulating catecholamines. In addition to these stimuli, mechanical stretch also stimulates secretion from ATII cells. Indeed, stretch may regulate multiple responses in these cells, including proliferation, differentiation and cell death (Nicholas, 1993). To study the effects of stretch on ATII cells, investigators have used an increasingly sophisticated array of in vivo and in vitro models in which cells are subjected to various expansion and stretch regimens. Herein I review the various models that have been used to study the effects of stretch on ATII cells and summarize our current understanding of how this stimulus is thought to regulate ATII cell function at both the molecular and cellular level in the lung.

Section snippets

ATII cells

ATII cells are small cuboidal cells that comprise approximately 10% of the alveolar epithelial surface area in the lung (Mason and Shannon, 1997). They are preferentially located in corners of the epithelium, where they form tight junctions with neighboring ATI cells, which are large flattened gas-exchange cells that make up the remaining 90% of the epithelial surface area. ATII cells have several functions, the predominant two of which are: (1) the synthesis and secretion of surfactant; and

Stretch stimulation of ATII cells

ATII cells in the lung are subjected to mechanical distortion during development, normal breathing and clinical ventilation. Researchers have studied the effects that such distortion have on ATII cell activity using a variety of in vivo and in vitro models.

Conclusion

A diverse range of in vitro models have been used to examine the effects of stretch on ATII cell function. These models have varied in: (1) the types of stretch devices and stretch regimens used; (2) the culturing conditions; and (3) the origins of the ATII cells, with investigators utilizing primary cultures, ATII-derived cell lines, as well as cells from fetal and adult sources. Through this work, there has been significant progress in our understanding of how stretch affects the activity of

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      We found that the alveolar cells cultured at ALI express very low detectable levels of surfactant C when cultured in static conditions without fibroblasts (Fig. 6, c; Fig. S6.2, a), whereas, culture in the Open-Top Chip with fibroblasts and under mechanical stretching resulted in enhanced secretion of surfactant C in the effluent collected from the epithelial channel (Fig. 6, c). Similar findings on the regulation of cell secretory function have been reported previously in other systems [69,70]. Gene expression analysis confirmed that the synthesis of surfactant B and podoplanin were stimulated in the presence of fibroblasts (Fig. S6.1), while exposure to stretching sustained the expression of important alveolar tissue-specific makers including surfactant C (Fig. S6.2).

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