Glial-derived neurotrophic factor in human airway smooth muscle.
Glial-derived neurotrophic factor in human airway smooth muscle.
复制标题
DOI：
10.1002/jcp.30489
复制
发表时间：
2021-12
影响因子：
5.6
通讯作者：
Prakash YS
中科院分区：
文献类型：
--
作者：
Bhallamudi S;Roos BB;Teske JJ;Wicher SA;McConico A;M Pabelick C;Sathish V;Prakash YS
气道平滑肌（ASM）细胞通过产生炎症介质和生长因子（包括经典的神经营养因子，如BDNF）来调节局部气道环境。胶质细胞源性神经营养因子（GDNF）配体家族（GFL）是一种非经典的神经营养因子，其在气道中的作用尚不清楚。主要的GFLs，GDNF和Neurturin（NRTN）分别与GDNF家族受体α1（GFRα1）和GFRα2结合，GFR α 1和GFRα2与Ret受体配对以完成信号传导。在本研究中，我们发现GDNF在人肺中表达，并且在成人哮喘中表达增加，而人ASM表达GDNF及其受体。因此，我们使用人ASM细胞来检验ASM表达和GFLs的自分泌信号调节[Ca 2 +]i的假设。将来自非哮喘患者的去除血清的ASM细胞暴露于10 ng/ml GDNF或NRTN 15 min（急性）或24 h（慢性）。在fura-2负载的细胞中，急性GDNF或NRTN单独诱导[Ca 2 +]i反应，并进一步增强对1μM ACh或10μM组胺的反应。Ret抑制剂（SPP 86; 10 µM）或特异性GDNF螯合剂GFRα1-Fc（1µg/ml）显示了这些受体在GDNF效应中的作用。相反，NRTN不增强[Ca ~（2+）]i对组胺的反应。此外，非哮喘和哮喘ASM细胞的条件培养基显示GDNF分泌。与载体相比，SPP 86、Ret抑制剂和GFRa 1-Fc螯合剂显著降低[Ca 2 +]i反应，突出了分泌的GDNF的自分泌效应。慢性GDNF治疗增加组胺诱导的肌球蛋白轻链磷酸化。这些新的数据表明GFLs，特别是GDNF/GFRα1影响ASM [Ca 2 +]i，并提高了GFLs是气道高反应性的潜在靶点的可能性。
Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as BDNF. The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are non-classical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor α1 (GFRα1) and GFRα2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca2+]i. Serum-deprived ASM cells from non-asthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura-2 loaded cells, acute GDNF or NRTN alone induced [Ca2+]i responses, and further enhanced responses to 1µM ACh or 10µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1-Fc (1µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca2+]i response to histamine. Furthermore, conditioned media of non-asthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRa1-Fc chelator markedly decreased [Ca2+]i response compared to vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine-induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca2+]i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness.
登录
查看更多内容
DOI：
10.1152/ajplung.00206.2019
发表时间：
2020-01-01
影响因子：
4.9
作者：
Bhallamudi, Sangeeta;Connell, Jennifer;Sathish, Venkatachalem
通讯作者：
Sathish, Venkatachalem
DOI：
10.1183/09031936.00093314
发表时间：
2015-01
期刊：
The European respiratory journal
影响因子：
--
作者：
Dijkstra AE;Boezen HM;van den Berge M;Vonk JM;Hiemstra PS;Barr RG;Burkart KM;Manichaikul A;Pottinger TD;Silverman EK;Cho MH;Crapo JD;Beaty TH;Bakke P;Gulsvik A;Lomas DA;Bossé Y;Nickle DC;Paré PD;de Koning HJ;Lammers JW;Zanen P;Smolonska J;Wijmenga C;Brandsma CA;Groen HJ;Postma DS;LifeLines Cohort Study group
通讯作者：
LifeLines Cohort Study group
影响因子：
6.1
作者：
Chaudhuri, R;McMahon, AD;Thomson, NC
通讯作者：
Thomson, NC
影响因子：
16.2
作者：
Heuckeroth, RO;Enomoto, H;Milbrandt, J
通讯作者：
Milbrandt, J
DOI：
10.1152/ajplung.00580.2016
发表时间：
2017-08-01
影响因子：
4.9
作者：
Freeman, Michelle R.;Sathish, Venkatachalem;Prakash, Y. S.
通讯作者：
Prakash, Y. S.