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      Emergence of airway smooth muscle mechanical behavior through dynamic reorganization of contractile units and force transmission pathways.

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          Abstract

          Airway hyperresponsiveness (AHR) in asthma remains poorly understood despite significant research effort to elucidate relevant underlying mechanisms. In particular, a significant body of experimental work has focused on the effect of tidal fluctuations on airway smooth muscle (ASM) cells, tissues, lung slices, and whole airways to understand the bronchodilating effect of tidal breathing and deep inspirations. These studies have motivated conceptual models that involve dynamic reorganization of both cytoskeletal components as well as contractile machinery. In this article, a biophysical model of the whole ASM cell is presented that combines 1) crossbridge cycling between actin and myosin; 2) actin-myosin disconnectivity, under imposed length changes, to allow dynamic reconfiguration of "force transmission pathways"; and 3) dynamic parallel-to-serial transitions of contractile units within these pathways that occur through a length fluctuation. Results of this theoretical model suggest that behavior characteristic of experimentally observed force-length loops of maximally activated ASM strips can be explained by interactions among the three mechanisms. Crucially, both sustained disconnectivity and parallel-to-serial transitions are necessary to explain the nature of hysteresis and strain stiffening observed experimentally. The results provide strong evidence that dynamic rearrangement of contractile machinery is a likely mechanism underlying many of the phenomena observed at timescales associated with tidal breathing. This theoretical cell-level model captures many of the salient features of mechanical behavior observed experimentally and should provide a useful starting block for a bottom-up approach to understanding tissue-level mechanical behavior.

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          Author and article information

          Journal
          J Appl Physiol (1985)
          Journal of applied physiology (Bethesda, Md. : 1985)
          American Physiological Society
          1522-1601
          0161-7567
          Apr 15 2014
          : 116
          : 8
          Affiliations
          [1 ] School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom.
          Article
          japplphysiol.01209.2013
          10.1152/japplphysiol.01209.2013
          4035787
          24481961
          1331bf39-7978-44cc-bd8b-892f3fe7281a
          History

          actin-myosin connectivity,contractile machinery,filament overlap,parallel-to-serial transitions

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