G Protein βγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma.
G Protein βγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma.
复制标题
DOI：
10.1371/journal.pone.0032078
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Grunstein MM
中科院分区：
文献类型：
--
作者：
Nino G;Hu A;Grunstein JS;McDonough J;Kreiger PA;Josephson MB;Choi JK;Grunstein MM
鉴于Gi蛋白Gβγ亚基在调节免疫和炎症反应中的重要作用，本研究探讨了Gβγ信号在过敏性哮喘家兔气道高反应性（AHR）诱导中的作用及其机制。相对于非致敏动物，吸入OVA激发的OVA致敏兔表现出AHR、肺部炎症、BAL中IL-13水平升高和气道磷酸二酯酶-4（PDE 4）活性增加。这些促哮喘反应可被吸入性膜渗透性抗G βγ阻断肽预处理所抑制，类似于糖皮质激素预处理的抑制作用。进一步的机制研究表明：（1）在用OVA致敏+激发的兔血清或IL-13致敏的离体气道平滑肌（ASM）中，相应的哮喘前收缩性变化也是Gβγ依赖性的，并由MAPK上调的PDE 4活性介导; 2）后者是由于Gβγ直接刺激非受体酪氨酸激酶c-Src，导致ERK 1/2的下游激活及其随后的PDE 4的转录上调。总的来说，这些数据是第一个确定涉及Gβγ诱导的c-Src直接激活的机制，导致ERK 1/2介导的PDE 4活性上调，在调节过敏性气道疾病兔模型中AHR和炎症的诱导中起决定性作用。
Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.
登录
查看更多内容
影响因子：
20.1
作者：
Casey LM;Pistner AR;Belmonte SL;Migdalovich D;Stolpnik O;Nwakanma FE;Vorobiof G;Dunaevsky O;Matavel A;Lopes CM;Smrcka AV;Blaxall BC
通讯作者：
Blaxall BC
影响因子：
4.4
作者：
Druey, Kirk M.
通讯作者：
Druey, Kirk M.
影响因子：
4.8
作者：
Chang, M;Zhang, LS;Sanders-Bush, E
通讯作者：
Sanders-Bush, E
影响因子：
4.1
作者：
Conway, AM;Rakhit, S;Pyne, NJ
通讯作者：
Pyne, NJ
DOI：
10.1111/j.1365-2125.1986.tb02956.x
发表时间：
1986-12-01
影响因子：
3.4
作者：
GOLDIE, RG;SPINA, D;PATERSON, JW
通讯作者：
PATERSON, JW