Kumawat Kuldeep, Koopmans Tim, Gosens Reinoud
University of Groningen, Groningen Research Institute for Asthma and COPD, Department of Molecular Pharmacology , A. Deusinglaan 1, 9713 AV Groningen , The Netherlands +31 50 363 8177 ; +31 50 363 6908 ;
Expert Opin Ther Targets. 2014 Sep;18(9):1023-34. doi: 10.1517/14728222.2014.934813. Epub 2014 Jul 8.
Pathological alteration in the airway structure, termed as airway remodeling, is a hallmark feature of individuals with asthma and has been described to negatively impact lung function in asthmatics. Recent studies have raised considerable interest in the regulatory role of β-catenin in remodeling asthmatic airways. The WNT/β-catenin signaling pathway is the key to normal lung development and tightly coordinates the maintenance of tissue homeostasis under steady-state conditions. Several studies indicate the crucial role of β-catenin signaling in airway remodeling in asthma and suggest that this pathway may be activated by both the growth factors and mechanical stimuli such as bronchoconstriction.
In this review, we discuss recent literature regarding the mechanisms of β-catenin signaling activation and its mechanistic role in asthmatic airway remodeling. Further, we discuss the possibilities of therapeutic targeting of β-catenin.
The aberrant activation of β-catenin signaling by both WNT-dependent and -independent mechanisms in asthmatic airways plays a key role in remodeling the airways, including cell proliferation, differentiation, tissue repair and extracellular matrix production. These findings are interesting from both a mechanistic and therapeutic perspective, as several drug classes have now been described that target β-catenin signaling directly.
气道结构的病理改变,即气道重塑,是哮喘患者的一个标志性特征,并且已被描述为对哮喘患者的肺功能产生负面影响。最近的研究引起了人们对β-连环蛋白在哮喘气道重塑中的调节作用的极大兴趣。WNT/β-连环蛋白信号通路是正常肺发育的关键,并且在稳态条件下紧密协调组织稳态的维持。多项研究表明β-连环蛋白信号在哮喘气道重塑中起关键作用,并提示该通路可能被生长因子和诸如支气管收缩等机械刺激所激活。
在本综述中,我们讨论了关于β-连环蛋白信号激活机制及其在哮喘气道重塑中的作用机制的最新文献。此外,我们还讨论了β-连环蛋白治疗靶点的可能性。
在哮喘气道中,通过WNT依赖和非依赖机制导致的β-连环蛋白信号异常激活在气道重塑中起关键作用,包括细胞增殖、分化、组织修复和细胞外基质产生。从机制和治疗角度来看,这些发现都很有趣,因为现在已经描述了几类直接靶向β-连环蛋白信号的药物。