Abstract
Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma.
Highlights
Airway smooth muscle cell contraction and proliferation contribute to the pathogenesis of airway hyperresponsiveness (AHR) and airway remodeling [1,2,3,4,5,6,7,8], cardinal features of asthma that affect nearly 25 million people in the United Sates and 250 million people worldwide
Expression of a charge-neutralizing cortactin mutant inhibits contraction and actin dynamics during agonist activation [111]. These results suggest a novel paradigm for the regulation of actin dynamics in smooth muscle: Upon contractile activation, HDAC8 induces cortactin deacetylation, which in turn promotes actin polymerization and the contraction in airway smooth muscle (Fig. 2)
Actin polymerization has a positive role in regulating the recruitment of β-catenin to N-cadherin. These findings reveal a novel role of adherens junctions in smooth muscle contraction: Contractile stimulation promotes actin polymerization, which may increase the coupling of β-catenin with N-cadherin and facilitate intercellular mechanotransduction (Fig. 3)
Summary
Airway smooth muscle cell contraction and proliferation contribute to the pathogenesis of airway hyperresponsiveness (AHR) and airway remodeling [1,2,3,4,5,6,7,8], cardinal features of asthma that affect nearly 25 million people in the United Sates and 250 million people worldwide (www.cdc.gov and www.who.int). These results suggest that actin filament polymerization and myosin activation are two parallel cellular processes that are fundamental for the regulation of smooth muscle contraction. Knockdown of Abl attenuates actin polymerization in smooth muscle cells/tissues during contractile stimulation [14, 17, 48].
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