Airway hyper-responsiveness in allergic asthma in guinea-pigs is mediated by nerve growth factor via the induction of substance P: a potential role for trkA
Airway hyper-responsiveness in allergic asthma in guinea-pigs is mediated by nerve growth factor via the induction of substance P: a potential role for trkA
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DOI：
10.1111/j.1365-2222.2006.02549.x
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发表时间：
2006-09-01
影响因子：
6.1
通讯作者：
Fischer, A.
中科院分区：
文献类型：
--
作者：
de Vries, A.;Engels, F.;Fischer, A.
背景神经营养因子神经生长因子（NGF）是过敏性哮喘的一种介导因子。直接证据表明，抑制神经生长因子诱导的神经营养因子受体的激活导致气道症状的改善是缺乏的。因此，我们研究的影响，抑制剂的神经生长因子信号转导的气道高反应性（AHR）和肺部炎症的豚鼠过敏性asthma.Methods模型的发展，气道反应性收缩激动剂组胺在体内豚鼠致敏和卵清蛋白（OVA）的挑战。测定支气管肺泡灌洗液（BALF）中炎性细胞内流和NGF水平。P物质，炎症的关键介质，测定肺组织中的放射免疫测定法，而P物质的免疫反应神经元在结状神经节测定免疫组化。结果OVA激发诱导AHR后24小时，在OVA致敏的豚鼠。这与BALF中NGF含量的增加相吻合。同时，P物质免疫反应阳性神经元的比例增加，在肺组织中的P物质的数量增加，我们用酪氨酸激酶抑制剂阻断高亲和力的神经生长因子受体，酪氨酸激酶A（trkA）的信号转导。酪氨酸激酶抑制剂（K252a或tyrphostin AG879）治疗均抑制AHR的发展，并完全阻止结状神经节和肺组织中P物质的增加，而这两种抑制剂对基线气道阻力没有影响。无论是治疗K252a或tyrphostin AG879改变了炎症细胞在BALF中的流入，由于过敏原challenge.Conclusions，我们得出结论，P物质在我们的过敏性哮喘模型中的AHR的诱导中发挥作用，这是最有可能由NGF介导的。由于两种酪氨酸激酶抑制剂AG879和K252a在过敏原激发后对气道功能显示出相似的抑制作用，尽管两种酪氨酸激酶抑制剂对trkA酪氨酸激酶以外的靶点显示出不同的非特异性抑制作用，但很可能源自感觉神经的P物质的诱导是由NGF通过其高亲和力受体trkA介导的。
Background The neurotrophin nerve growth factor (NGF) has been implicated as a mediator in allergic asthma. Direct evidence that inhibition of NGF-induced activation of neurotrophin receptors leads to improvement of airway symptoms is lacking. We therefore studied the effects of inhibitors of NGF signal transduction on the development of airway hyper-responsiveness (AHR) and pulmonary inflammation in a guinea-pig model for allergic asthma.Methods Airway responsiveness to the contractile agonist histamine was measured in vivo in guinea-pigs that were sensitized and challenged with ovalbumin (OVA). Inflammatory cell influx and NGF levels were determined in bronchoalveolar lavage fluid (BALF). Substance P, a key mediator of inflammation, was measured in lung tissue by radioimmunoassay, while substance P immunoreactive neurons in nodose ganglia were measured by immunohistochemistry.Results OVA challenge induced an AHR after 24 h in OVA-sensitized guinea-pigs. This coincided with an increase in the amount of NGF in BALF. Simultaneously, an increase in the percentage of substance P immunoreactive neurons in the nodose ganglia and an increase in the amount of substance P in lung tissue were found. We used tyrosine kinase inhibitors to block the signal transduction of the high-affinity NGF receptor, tyrosine kinase A (trkA). Treatment with the tyrosine kinase inhibitors (K252a or tyrphostin AG879) both inhibited the development of AHR, and prevented the increase in substance P in the nodose ganglia and lung tissue completely whereas both inhibitors had no effect on baseline airway resistance. Neither treatment with K252a or tyrphostin AG879 changed the influx of inflammatory cells in the BALF due to allergen challenge.Conclusions We conclude that substance P plays a role in the induction of AHR in our model for allergic asthma which is most likely mediated by NGF. As both tyrosine kinase inhibitors AG879 and K252a show a similar inhibitory effect on airway function after allergen challenge, although both tyrosine kinase inhibitors exhibit different non-specific inhibitory effects on targets other than trkA tyrosine kinases, it is likely that the induction of substance P derived from sensory nerves is mediated by NGF via its high-affinity receptor trkA.