Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 314, Issue 5, Pages L799-L807Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00326.2017
Keywords
airway smooth muscle; cofilin; cytoskeleton; deep inspiration; fluidization; stretch
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Funding
- National Cancer Institute Grant [1U01-CA-202123]
- National Heart, Lung, and Blood Institute Grants [R01-HL-107561-01, PO1-HL-120839, R21-HL-123522, T32-HL-007118]
- Canadian Institutes of Health Operating Grants [MOP-13505, MOP-97988]
- Eye's High Fellowship Award (University of Calgary)
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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 actinsevering 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.
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