Introduction

While mechanotransduction within the cytoskeleton, cell membrane, and cell-matrix interface are well known, multicellular tissue organization provides an additional opportunity for mechanotransduction in the extracellular space through local autocrine signaling. In many tissues and organs, cells are organized into relatively dense structures separated by narrow interstitial spaces. The interstitial fluid in these spaces facilitates nutrient and waste transport, and provides a conduit for the exchange of autocrine and paracrine signals. When mechanical loads are applied to tissues, the resulting pressure gradients can locally redistribute interstitial fluid, altering the geometry of the interstitial spaces separating cells. These changes in interstitial geometry, in the presence of a constitutively active autocrine signaling environment, provide a means for coupling mechanical loading to changes in local ligand concentration and receptor activation. In this chapter we discuss these behaviors using the example of airway epithelial cells, which exhibit constitutive autocrine signaling localized to an interstitial space that deforms under physiological levels of loading. We highlight evidence demonstrating that changes in autocrine ligand concentration arising from the deformation of the local interstitial geometry are sufficient to drive alterations in receptor activation. We then use a computational modeling approach to explore the unique characteristics of this mechanical signaling system, and discuss its broader implications.

Mechanical Stress–Induced Signaling in Bronchial Epithelium

The mechanical environment shapes the development and function of the lung’s airways from the first stages of airway morphogenesis in utero (Tschumperlin and Drazen, 2006). In the adult lung the mechanical environment is defined by a unique balance of surface, tissue, and muscle forces, but the underlying load-bearing structure is similar to many organs of the body: an epithelium-lined structure surrounded by extracellular matrix, vasculature, and mesenchymal cells (e.g., smooth muscle). In diseases such as asthma, activation of the airway smooth muscle wrapped around airways abruptly narrows the airway lumen (Figure 14.1; Plate 16) and profoundly changes the stress state within the tissue of the airway wall (Wiggs et al., 1997). Because mechanical stress–induced remodeling is well known in many tissues, and tissue remodeling is frequently observed in asthmatic airways (Bousquet et al., 2000), two related question arise: Are the cells of the airway wall responsive to the mechanical stresses that accompany smooth muscle shortening (bronchoconstriction), and if so, how do the cells sense changes in their mechanical environment?