Selected contribution:: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KC1
Selected contribution:: TNF-α modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KC1
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DOI：
10.1152/japplphysiol.00140.2003
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发表时间：
2003-08-01
影响因子：
3.3
通讯作者：
Amrani, Y
中科院分区：
文献类型：
--
作者：
Chen, H;Tliba, O;Amrani, Y
虽然哮喘气道高反应性的机制是复杂的，涉及多种因素，现在的证据表明，气道平滑肌（ASM）的内在异常可能发挥重要作用。我们以前报道过，TNF-α，一种参与哮喘的细胞因子，在培养的ASM细胞中增强G蛋白偶联受体（GPCR）激动剂诱发的钙反应。在这里，我们已经扩大了我们以前的研究，调查是否TNF-α也调节收缩和舒张反应GPCR激活培养小鼠气管环。我们发现，在用50 ng/ml TNF-α处理的气管环中，卡巴胆碱诱导的等长收缩力比单独用稀释剂处理的气管环显著增加30%（P < 0.05）。TNF-α还使KCl诱导的力产生比单独用稀释剂处理的环增加70%（P < 0.01）。在从TNF-α受体（TNFR）1缺陷小鼠获得的气管环和仅激活TNFR 2的TNF-α突变体处理的对照环中，TNF-α对卡巴胆碱诱导的等长力产生的增强作用完全消失。TNF-α也减弱了对异丙肾上腺素的舒张反应，但对PGE（2）或毛喉素没有影响。TNF-α对GPCR诱导的ASM反应性的调节作用被百日咳毒素完全消除，百日咳毒素是G（i）α蛋白的抑制剂。总之，这些数据表明，TNF-α可能通过调节ASM对收缩和β-肾上腺素受体GPCR激动剂的反应性参与哮喘气道高反应性的发展。
Although the mechanisms that underlie airway hyperresponsiveness in asthma are complex and involve a variety of factors, evidence now suggests that intrinsic abnormalities in airway smooth muscle (ASM) may play an important role. We previously reported that TNF-alpha, a cytokine involved in asthma, augments G-protein-coupled receptor ( GPCR) agonist-evoked calcium responses in cultured ASM cells. Here we have extended our previous studies by investigating whether TNF-alpha also modulates the contractile and relaxant responses to GPCR activation using cultured murine tracheal rings. We found that in tracheal rings treated with 50 ng/ml TNF-alpha, carbachol-induced isometric force was significantly increased by 30% compared with those treated with diluent alone ( P < 0.05). TNF-α also augmented KCl-induced force generation by 70% compared with rings treated with diluent alone (P < 0.01). The enhancing effect of TNF-alpha on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF-alpha receptor (TNFR) 1-deficient mice and in control rings treated with a TNF-alpha mutant that solely activates TNFR2. TNF-alpha also attenuated relaxation responsiveness to isoproterenol but not to PGE(2) or forskolin. TNF-alpha modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of G(i)alpha proteins. Taken together, these data suggest that TNF-alpha may participate in the development of airway hyperresponsiveness in asthma via the modulation of ASM responsiveness to both contractile and beta-adrenoceptor GPCR agonists.