Wu Yidi, Huang Youliang, Gunst Susan J
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
Am J Physiol Lung Cell Mol Physiol. 2016 Nov 1;311(5):L893-L902. doi: 10.1152/ajplung.00299.2016. Epub 2016 Sep 9.
The effects of mechanical forces and focal adhesion kinase (FAK) in regulating the inflammatory responses of airway smooth muscle (ASM) tissues to stimulation with interleukin (IL)-13 were investigated. Canine tracheal tissues were subjected to different mechanical loads in vitro, and the effects of mechanical load on eotaxin secretion and inflammatory signaling pathways in response to IL-13 were determined. Eotaxin secretion by tissues in response to IL-13 was significantly inhibited in muscles maintained at a higher (+) load compared with those at a lower (-) load as assessed by ELISA, and Akt activation was also reduced in the higher (+) loaded tissues. Conversely the (+) mechanical load increased activation of the focal adhesion proteins FAK and paxillin in the tissues. The role of FAK in regulating the mechanosensitive responses was assessed by overexpressing FAK-related nonkinase in the tissues, by expressing the FAK kinase-dead mutant FAK Y397F, or by treating tissues with the FAK inhibitor PF-573228. FAK inactivation potentiated Akt activity and increased eotaxin secretion in response to IL-13. FAK inhibition also suppressed the mechanosensitivity of Akt activation and eotaxin secretion. In addition, FAK inactivation suppressed smooth muscle myosin heavy chain expression induced by the higher (+) mechanical load. The results demonstrate that the imposition of a higher mechanical load on airway smooth muscle stimulates FAK activation, which promotes the expression of the differentiated contractile phenotype and suppresses the synthetic phenotype and the inflammatory responses of the muscle tissue.
研究了机械力和粘着斑激酶（FAK）在调节气道平滑肌（ASM）组织对白细胞介素（IL）-13刺激的炎症反应中的作用。对犬气管组织进行体外不同机械负荷处理，并确定机械负荷对响应IL-13时嗜酸性粒细胞趋化因子分泌和炎症信号通路的影响。通过酶联免疫吸附测定法（ELISA）评估，与低（-）负荷的肌肉相比，高（+）负荷下的组织中，响应IL-13时组织分泌的嗜酸性粒细胞趋化因子显著受到抑制，并且高（+）负荷组织中的Akt激活也降低。相反，（+）机械负荷增加了组织中粘着斑蛋白FAK和桩蛋白的激活。通过在组织中过表达FAK相关非激酶、表达FAK激酶失活突变体FAK Y397F或用FAK抑制剂PF-573228处理组织，评估了FAK在调节机械敏感反应中的作用。FAK失活增强了Akt活性，并增加了响应IL-13时的嗜酸性粒细胞趋化因子分泌。FAK抑制还抑制了Akt激活和嗜酸性粒细胞趋化因子分泌的机械敏感性。此外，FAK失活抑制了由高（+）机械负荷诱导的平滑肌肌球蛋白重链表达。结果表明，对气道平滑肌施加较高的机械负荷会刺激FAK激活，这促进了分化收缩表型的表达，并抑制了肌肉组织的合成表型和炎症反应。
