PDF(Pubmed)
Abstract：
Asthma is a chronic inflammatory disorder of the lower airways characterized by modulation of airway smooth muscle (ASM) function. Infiltration of smooth muscle by inflammatory mediators is partially regulated by transmembrane integrins and the major smooth muscle laminin receptor α7β1 integrin plays a critical role in the maintenance of ASM phenotype. The goal of the current study was to investigate the role of α7 integrin in asthma using smooth muscle-specific α7 integrin transgenic mice (TgSM-Itgα7) using both acute and chronic OVA sensitization and challenge protocols that mimic mild to severe asthmatic phenotypes. Transgenic over-expression of the α7 integrin in smooth muscle resulted in a significant decrease in airway resistance relative to controls, reduced the total number of inflammatory cells and substantially inhibited the production of crucial Th2 and Th17 cytokines in airways. This was accompanied by decreased secretion of various inflammatory chemokines such as eotaxin/CCL11, KC/CXCL3, MCP-1/CCL2, and MIP-1β/CCL4. Additionally, α7 integrin overexpression significantly decreased ERK1/2 phosphorylation in the lungs of TgSM-Itgα7 mice and affected proliferative, contractile, and inflammatory downstream effectors of ERK1/2 that drive smooth muscle phenotype in the lung. Taken together, these results support the hypothesis that enhanced expression of α7 integrin in vivo inhibits allergic inflammation and airway resistance. Moreover, we identify ERK1/2 as a potential target by which α7 integrin signals to regulate airway inflammation. We conclude that identification of therapeutics targeting an increase in smooth muscle α7 integrin expression could serve as a potential novel treatment for asthma.
摘要：
哮喘是下气道的慢性炎性病症,其特征在于气道平滑肌(ASM)功能的调节。炎症介质对平滑肌的浸润受跨膜整联蛋白的部分调节，主要的平滑肌层粘连蛋白受体α7β1整联蛋白在维持ASM表型中起关键作用。本研究的目的是使用平滑肌特异性α7整合素转基因小鼠（TgSM-Itgα7），使用模拟轻度至重度哮喘表型的急性和慢性OVA敏化和激发方案，研究α7整合素在哮喘中的作用。α7整合素在平滑肌中的转基因过表达导致气道阻力相对于对照显著降低,减少了炎症细胞的总数，并基本上抑制了气道中关键Th2和Th17细胞因子的产生。这伴随着各种炎性趋化因子如eotaxin/CCL11、KC/CXCL3、MCP-1/CCL2和MIP-1β/CCL4的分泌减少。此外,α7整合素过表达显著降低TgSM-Itgα7小鼠肺内ERK1/2磷酸化,收缩，和驱动肺平滑肌表型的ERK1/2的炎症下游效应子。一起来看,这些结果支持以下假设：体内α7整合素的表达增强会抑制过敏性炎症和气道阻力。此外，我们确定ERK1/2是α7整合素信号调节气道炎症的潜在靶点.我们得出的结论是，针对平滑肌α7整合素表达增加的治疗方法的鉴定可能是哮喘的潜在新型治疗方法。
