| Autor: |
Lan B; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts.; Smooth Muscle Research Group and Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada., Krishnan R; Center for Vascular Biology Research, Department of Emergency Medicine, Beth Israel Deaconess Medical Center , Boston, Massachusetts., Park CY; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts., Watanabe RA; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts., Panganiban R; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts., Butler JP; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts.; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts., Lu Q; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts., Cole WC; Smooth Muscle Research Group and Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada., Fredberg JJ; Department of Environmental Health, Harvard T. H. Chan School of Public Health , Boston, Massachusetts. |
| Abstrakt: |
With every deep inspiration (DI) or sigh, the airway wall stretches, as do the airway smooth muscle cells in the airway wall. In response, the airway smooth muscle cell undergoes rapid stretch-induced cytoskeletal fluidization. As a molecular mechanism underlying the cytoskeletal fluidization response, we demonstrate a key role for the actin-severing protein cofilin. Using primary human airway smooth muscle cells, we simulated a DI by imposing a transient stretch of physiological magnitude and duration. We used traction microscopy to measure the resulting changes in contractile forces. After a transient stretch, cofilin-knockdown cells exhibited a 29 ± 5% decrease in contractile force compared with prestretch conditions. By contrast, control cells exhibited a 67 ± 6% decrease ( P < 0.05, knockdown vs. control). Consistent with these contractile force changes with transient stretch, actin filaments in cofilin-knockdown cells remained largely intact, whereas actin filaments in control cells were rapidly disrupted. Furthermore, in cofilin-knockdown cells, contractile force at baseline was higher and rate of remodeling poststretch was slower than in control cells. Additionally, the severing action of cofilin was restricted to the release phase of the transient stretch. We conclude that the actin-severing activity of cofilin is an important factor in stretch-induced cytoskeletal fluidization and may account for an appreciable part of the bronchodilatory effects of a DI. |
