cells in the lung are normally subjected to a variety of mechanical forces as a result of the dynamic nature of lung function. Cells comprising the lung parenchyma, the airways, and the pulmonary and bronchial vascular systems experience a wide range of physical forces associated with lung inflation, vascular perfusion, and physical activity. One form of mechanical stress is termed shear stress. Shear stress is generated when fluids such as blood or air move across a cell surface, thereby generating a force parallel to the plasma membrane that produces a tangential distortion of the cell. Such shearing forces occur in the conducting airways, due to airflow, and in the vascular systems as a consequence of blood flow. They can also potentially occur in alveoli under the pathophysiological condition where edema fluid floods the air space. During positive-pressure ventilation, those alveoli can undergo rapid and cyclic transitions from being small and flooded at end exhalation to being large and air-filled at end inspiration. That transition can generate significant shear stress at the alveolar surface as the edema fluid redistributes and the alveolar volume changes.
A second form of mechanical distortion is referred to as mechanical strain. Strain occurs when a force is applied to an elastic cell, causing a mechanical stretch or distortion. Although it has been argued that alveoli tend to increase their volume during inhalation by unfolding pleats rather than by stretching alveoli (2), it is clear that force must be transmitted from the pleural space through the lung to the alveolar wall to overcome the elastic recoil during normal breathing. These forces create tension in the alveolar septa and, therefore, produce mechanical strain of the cells that transmit the force. In pathophysiological states such as acute lung injury where lung elastic recoil is increased, the magnitude of these forces is increased, and the degree of strain is altered.
A third and often overlooked form of mechanical distortion in the lung can occur during bronchoconstriction in patients with asthma. The constriction of smooth muscle cells in the airway generates a compressive force in the mucosa, resulting in the buckling of the airway epithelium. The paper by Tschumperlin and colleagues (11) in this issue illustrates the potential importance of this form of mechanical strain in terms of its ability to activate the mitogen-activated protein (MAP) kinase signaling pathway.
Cells subjected to strain or shear stress exhibit a diverse and extensive range of responses. The articles in this issue's special topic focus on pressure-induced calcium signals in pulmonary cells (7a, 11b), stretch-induced activation of MAP kinase and G proteins in alveolar epithelial cells (3), stretch-induced activation of gene expression in pulmonary artery smooth muscle cells (9), and compression-induced changes in MAP kinase signaling and gene expression in bronchial epithelial cells (11). A number of excellent reviews are available and should be consulted for a more comprehensive analysis of the many signaling pathways that become activated in response to mechanical strain (4–6, 8, 11a).
The “holy grail” of mechanotransduction continues to be the identity and molecular mechanism of the mechanosensor(s) in cells. The mechanosensor is defined as the system that detects the mechanical strain on the cell and converts this distortion into a biological signal. Candidate mechanisms that have been described include stretch-sensitive ion channels, integrin-cytoskeletal interactions, nuclear-cytoskeletal interactions, reactive oxygen species generators, and other putative systems. Part of the problem in identifying the most upstream step in the mechanosensing process is that it has been difficult to know whether a particular activated step represents the sensor itself or a downstream target that is activated by the sensor. Even subcellular approaches such as patch clamping may be influenced by the presence of a mechanosensor protein or organelle that remains attached to the membrane patch (10). Attempts to provide more definitive answers by creating transgenic animals with targeted knockout of key cytoskeletal proteins often result in embryonic lethality, due to the critical functions contributed by these proteins (7, 12). So the quest continues, and success will likely require the collaboration of molecular biologists, integrative biologists, and biomedical engineers. Interest in the process of mechanotransduction in the lung continues to grow. Table1 shows the number of papers identified in Medline using the search terms “mechanotransduction” and “lung or pulmonary” over the past 30 years.
Despite the growing interest, some investigators might still have believed that mechanotransduction in the lung was not important, until the Acute Respiratory Distress Syndrome Network study demonstrated that mechanical ventilation of patients with tidal volumes of 6 instead of 12 ml/kg resulted in a significant decrease in morbidity and mortality (1). Our understanding of the significance of mechanical strain in the lung has progressed beyond the early view that stretch only affects the lung when it causes mechanical failure of the structural elements. We have just begun to understand the diverse set of responses that are selectively triggered by mechanical strain within the physiological range. Importantly, there is no longer any doubt about the importance of mechanical distortion in the physiology or the pathophysiology of the lung.
- Copyright © 2002 the American Physiological Society