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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/L479    most recent 00421.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fairbank, N. J. Articles by Maksym, G. N. PubMed PubMed Citation Articles by Fairbank, N. J. Articles by Maksym, G. N.

Airway smooth muscle cell tone amplifies contractile function in the presence of chronic cyclic strain

¹School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada; ²Department of Medical Engineering, University of Applied Sciences Wilhelmshaven, Wilhelmshaven, Germany; ³National 985 Project, Institute of Biorheology and Gene Regulation, Bioengineering College, Chongqing University, Chongqing, China; and ⁴Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

Submitted 11 October 2007 ; accepted in final form 23 June 2008

Chronic contractile activation, or tone, in asthma coupled with continuous stretching due to breathing may be involved in altering the contractile function of airway smooth muscle (ASM). Previously, we (11) showed that cytoskeletal remodeling and stiffening responses to acute (2 h) localized stresses were modulated by the level of contractile activation of ASM. Here, we investigated if altered contractility in response to chronic mechanical strain was dependent on repeated modulation of contractile tone. Cultured human ASM cells received 5% cyclic (0.3 Hz), predominantly uniaxial strain for 5 days, with once-daily dosing of either sham, forskolin, carbachol, or histamine to alter tone. Stiffness, contractility (KCl), and "relaxability" (forskolin) were then measured as was cell alignment, myosin light-chain phosphorylation (pMLC), and myosin light-chain kinase (MLCK) content. Cells became aligned and baseline stiffness increased with strain, but repeated lowering of tone inhibited both effects (P < 0.05). Strain also reversed a negative tone-modulation dependence of MLCK, observed in static conditions in agreement with previous reports, with strain and tone together increasing both MLCK and pMLC. Furthermore, contractility increased 176% (SE 59) with repeated tone elevation. These findings indicate that with strain, and not without, repeated tone elevation promoted contractile function through changes in cytoskeletal organization and increased contractile protein. The ability of repeated contractile activation to increase contractility, but only with mechanical stretching, suggests a novel mechanism for increased ASM contractility in asthma and for the role of continuous bronchodilator and corticosteroid therapy in reversing airway hyperresponsiveness.

asthma; mechanical stress; cytoskeletal remodeling; myosin light-chain kinase; optical magnetic twisting cytometry