© 2005 American Thoracic Society DOI: 10.1165/rcmb.F297
When Wheeze Leads to SqueezeGrowth under PressureUniversity of Cincinnati Cincinnati, Ohio
In this issue of the Journal (pp. 373–380), Chu and colleagues examine the consequences to the airway epithelium of compressive stress, much like that generated during bronchoconstriction in asthma (1). Compressive and tensile stress have been studied extensively in muscle and bone tissue culture (2), and exciting theories have been advanced as to how it may control the fate of stem cells (3). Much less is certain about the role of the stresses in airway diseases. Previously, these investigators reported that compressive stress led to phosphorylation of epidermal growth factor receptor (EGFR), with a subsequent increase in of heparin-binding epidermal growth factor-like growth factor (HB-EGF) transcripts and immunostaining protein (4). Triggered by stimuli of cell proliferation, membrane-bound EGF family ligands are cleaved by matrix metalloproteinases (MMP) and thus shed to bind to EGFR, leading to phosphorylation. Thus, this process of EGFR-activation The mechanisms by which compressive stress leads to EGFR activation are unknown. However, these investigators have proposed that it is due to compression of the lateral intercellular space (LIS) surrounding epithelial cells (7). Assuming a constant shedding rate into a collapsing volume, local ligand concentrations could theoretically increase sufficiently to account for the observed receptor signaling. They also suggest that this effect is not due to osmotic stress response, which activated additional mitogen-activated protein kinases. Although this "LIS squeeze" theory has merits, one could image other possible explanations for the role of other mechanisms triggering mechanotransduction. For example, specialized mechanosensory cells function in many tissues through stretch-activated gated ion channels (8, 9). Cytoskeletal–integrin interactions can activate growth factors possibly through focal adhesion complexes or cell–cell adherens junctions, which have been discussed as mechnosensors leading to altered transcriptional programming (10). In this new study, findings are broadened to other EGF family members, including epiregulin (which is detected as transcript and protein) and amphiregulin (transcript alone). Transient stress of only a few minutes triggers a response lasting several hours, suggesting long-term consequences of bouts of bronchospasm. However, this process seems to wane when continuous compression is extended past 4 h, suggesting that the existence of an "off" mechanism yet to be discovered. Regulation of the stop signal obviously may be critical in many biological processes, including organogenesis, hyperplasia, and tumorigenesis. In all these processes, coordinated growth achieves the desired size, shape, and function. In contrast, nonuniformity resulting from either the lack of cells to stop growing or other cells to keep up with growth ("cell competition") leads to mounting mechanical stress, which may trigger these feedback signals that regulate cell division and ensure stability of growth (11). In a pseudostratified environment, understanding the possible mechanisms by which the epithelial cells communicate with their environment, transduce stress, grow and stop growing, and differentiate remains a fascinating open question. Footnotes Conflict of Interest Statement: G.D.L. has no declared conflicts of interest; H.S.D. has no declared conflicts of interest. References
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ligand transcription