Cytoskeletal remodeling of the airway smooth muscle cell: a mechanism for adaptation to mechanical forces in the lung

Abstract

Airway smooth muscle is continuously subjected to mechanical forces caused by changes in lung volume during breathing. These mechanical oscillations have profound effects on airway smooth muscle contractility both in vivo and in vitro. Alterations in airway smooth muscle properties in response to mechanical forces may result from adaptive changes in the organization of the actin cytoskeleton. Recent advances suggest that in airway smooth muscle, two cytosolic signaling proteins that associate with focal adhesion complexes, focal adhesion kinase (FAK) and paxillin, are involved in transducing external mechanical signals. FAK and paxillin regulate changes in the organization of the actin cytoskeleton and the activation of contractile proteins. Actin is in a dynamic state in airway smooth muscle and undergoes polymerization and depolymerization during the contraction–relaxation cycle. The organization of the cytoskeletal proteins, vinculin, talin, and α-actinin, which mediate linkages between actin filaments and transmembrane integrins, is also regulated by contractile stimulation in airway smooth muscle. The fluidity of the cytoskeletal structure of the airway smooth muscle cell may be fundamental to its ability to adapt and respond to the mechanical forces imposed on it in the lung during breathing.

Introduction

The smooth muscle of the airways is exposed to continuously changing mechanical conditions during normal breathing. As lung volume increases and decreases with each breath, the airways are subjected to forces that cause them to expand and contract, thereby stretching and retracting the airway smooth muscle. Airway smooth muscle is also periodically subjected to larger forces of expansion caused by intermittent deep breaths. The mechanical oscillations that occur during breathing are well-documented to have profound effects on airway tone and airway responsiveness in both humans and experimental animals (Fish et al., 1981, Nadel and Tierney, 1961, Tepper et al., 1995, Gunst et al., 2001, Warner and Gunst, 1992, Kapsali et al., 2000, King et al., 1999, Scichilone et al., 2000, Shinozuka et al., 1998). In both experimental animals and humans, the absence of tidal breathing or deep breaths increases airway responsiveness to a bronchoconstrictor challenge, and the imposition of volume oscillations or periodic deep breaths suppresses airway responsiveness and causes the dilation of contracted airways (Skloot et al., 1995, Warner and Gunst, 1992, Shen et al., 1997a, King et al., 1999, Salerno et al., 1999).

Isolated airways and airway smooth muscle in vitro mimic many of the characteristic responses to changes in lung volume that are observed in vivo (Shen et al., 1997b, Gunst, 1983, Gunst et al., 1990, Gunst and Wu, 2001, Fredberg et al., 1997, Wang et al., 2000). The responsiveness of isolated airways in vitro is reduced by subjecting them to volume oscillations (Gunst et al., 1990), and airway smooth muscle responsiveness is reduced by length or load oscillations (Gunst, 1983, Shen et al., 1997b, Fredberg et al., 1997). The effects of these oscillations on isolated airways and smooth muscle strips is fully reversible; responsiveness will eventually return to preoscillation levels after the oscillations are terminated. These observations suggest that the mechanisms by which the smooth muscle of the airways adapts and responds to mechanical forces play a critical role in regulating airway properties that are important to their physiologic function. The fact that many of the characteristics displayed by the airways in vivo are retained by isolated strips of airway smooth muscle in vitro suggests these behaviors reflect inherent properties of the airway smooth muscle cells, rather than responses to reflexes or humoral agents.

What are the mechanisms by which the function of airway smooth muscle is modulated in response to the forces of distortion imposed on it by external forces in its environment? In a number of non-muscle cell types, integrin-mediated signal transduction pathways have been shown to regulate processes of actin dynamics and reorganization that enable the cells to adjust to external mechanical forces by changes in their shape, stiffness, contractility and motility (Wang and Ingber, 1994, Schmidt et al., 1998, Wang et al., 1993, Shyy and Chien, 1997, Small et al., 1999). Recent evidence suggests that analogous signal transduction pathways are present in differentiated smooth muscle tissues, and that these pathways are important in initiating cytoskeletal processes that adapt the structural organization and contractile properties of smooth muscle tissues to external forces (Tang et al., 1999, Tang and Gunst, 2001b, Tang and Gunst, 2001a, Tang et al., 2002, Gerthoffer and Gunst, 2001, Ishida et al., 1999, Leduc and Meloche, 1995, Smith et al., 1998, Sul et al., 2001). Such processes may enable the smooth muscle tissues of hollow organs such as the airways to respond to a rapidly changing mechanical environment. In airway smooth muscle, cytoskeletal proteins involved in regulating the organization and structure of the actin cytoskeleton are mechanosensitive, and are regulated by contractile stimuli. These proteins play essential roles in mediating tension development, but the signaling pathways involved in their regulation can be activated independently of pathways that control crossbridge activation and crossbridge cycling. This review will address recent advances in our understanding of the cytoskeletal mechanisms by which airway smooth muscle cells adapt and respond to changes in external mechanical forces.