层粘连蛋白驱动促平滑肌收缩表型和气道高反应的存活信号
2013/07/23
摘要
气道平滑肌(ASM)增生与肥厚被认为是哮喘相对固定的气道高反应(AHR)的基础。因缺乏对收缩型平滑肌细胞增生和肥厚背后机制的了解，逆转气道重塑的治疗方法的发展受到阻碍。一种细胞外基质蛋白——层粘连蛋白表达增加与哮喘相关。我们的研究探讨层粘连蛋白诱导的ASM存活信号在ASM增生和AHR的发生发展中的作用。通过层粘连蛋白-选择性竞争肽——精氨酸（YIGSR）拮抗层粘连蛋白与整合素的连接，并使用外源性2-链层粘连蛋白模拟层粘连蛋白，我们得出，层粘连蛋白对于诱导ASM细胞存活是必要且充分的，伴有诱导平滑肌收缩表型的作用。利用siRNA，我们证实了层粘连蛋白结合整合素α7β1介导此过程。此外，层粘连蛋白-211-基因敲除小鼠中未能发现过敏原诱导的AHR。值得注意的是，哮喘气道的ASM 细胞内高表达细胞存活蛋白，这与ASM增生发展过程中降低细胞凋亡率的作用相一致。以层粘连蛋白-整合素α7β1的信号通路作为靶标有望为减少哮喘AHR的基础——收缩型ASM细胞增生与肥厚的疗法发展提供新途径。
Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity.
Tran T, Teoh CM, Tam JK, Qiao Y, Chin CY, Chong OK, Stewart AG, Harris T, Wong WS, Guan SP, Leung BP, Gerthoffer WT, Unruh H, Halayko AJ.
ABSTRACT I
ncreased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous 2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrinα7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrinα7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.
FASEB J. 2013 Jun 11. [Epub ahead of print]
气道平滑肌(ASM)增生与肥厚被认为是哮喘相对固定的气道高反应(AHR)的基础。因缺乏对收缩型平滑肌细胞增生和肥厚背后机制的了解，逆转气道重塑的治疗方法的发展受到阻碍。一种细胞外基质蛋白——层粘连蛋白表达增加与哮喘相关。我们的研究探讨层粘连蛋白诱导的ASM存活信号在ASM增生和AHR的发生发展中的作用。通过层粘连蛋白-选择性竞争肽——精氨酸（YIGSR）拮抗层粘连蛋白与整合素的连接，并使用外源性2-链层粘连蛋白模拟层粘连蛋白，我们得出，层粘连蛋白对于诱导ASM细胞存活是必要且充分的，伴有诱导平滑肌收缩表型的作用。利用siRNA，我们证实了层粘连蛋白结合整合素α7β1介导此过程。此外，层粘连蛋白-211-基因敲除小鼠中未能发现过敏原诱导的AHR。值得注意的是，哮喘气道的ASM 细胞内高表达细胞存活蛋白，这与ASM增生发展过程中降低细胞凋亡率的作用相一致。以层粘连蛋白-整合素α7β1的信号通路作为靶标有望为减少哮喘AHR的基础——收缩型ASM细胞增生与肥厚的疗法发展提供新途径。
(黄艳媚 摘译 邱晨 审校)
FASEB J. 2013 Jun 11. [Epub ahead of print]
FASEB J. 2013 Jun 11. [Epub ahead of print]
Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity.
Tran T, Teoh CM, Tam JK, Qiao Y, Chin CY, Chong OK, Stewart AG, Harris T, Wong WS, Guan SP, Leung BP, Gerthoffer WT, Unruh H, Halayko AJ.
ABSTRACT I
ncreased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous 2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrinα7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrinα7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.
FASEB J. 2013 Jun 11. [Epub ahead of print]
