Mohtasham Lida, Auais Alexander, Piedimonte Giovanni
Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9214, USA.
Pediatr Pulmonol. 2007 Jun;42(6):496-504. doi: 10.1002/ppul.20607.
Neurotrophic factors and receptors are upregulated in the respiratory tract of humans and rodents infected by the respiratory syncytial virus, leading to airway inflammation and hyperreactivity. The contribution of neurotrophic pathways to the recruitment of immuno-inflammatory cells and their response to anti-inflammatory therapy remains unclear. We sought to determine whether selective nerve growth factor inhibition prevents the immuno-inflammatory response against infection, and explored the effect of inhaled corticosteroids on virus-induced neurotrophic upregulation and the consequent recruitment of immuno-inflammatory cells into the airways. We tried to inhibit the recruitment of lymphocytes and monocytes into the airways of infected weanling rats using immunologic inhibition of nerve growth factor with a specific blocking antibody, or chemical inhibition of receptor tyrosine kinase with K252a. The anti-inflammatory activity of inhaled corticosteroids was studied in infected rats treated with budesonide, fluticasone, or vehicle. Immunological or chemical inhibition of nerve growth factor or its high-affinity receptor tyrosine kinase pathway inhibited the recruitment of inflammatory cells triggered by nociceptive irritation of infected rat airways, thereby reducing local and systemic immuno-inflammatory responses against the virus. Neurotrophic upregulation in infected airways was not affected by inhaled corticosteroids. As a logical consequence, these commonly used drugs were also unable to stop the recruitment of immune and inflammatory effector cells into infected airways. Overexpression of neurotrophic factors and receptors in airways infected by respiratory syncytial virus is critical for the development of airway inflammation and hyperreactivity, which is resistant to the anti-inflammatory effect of inhaled corticosteroids.
在感染呼吸道合胞病毒的人类和啮齿动物的呼吸道中，神经营养因子及其受体上调，导致气道炎症和高反应性。神经营养通路对免疫炎症细胞募集及其对抗炎治疗反应的作用仍不清楚。我们试图确定选择性抑制神经生长因子是否能预防针对感染的免疫炎症反应，并探讨吸入性糖皮质激素对病毒诱导的神经营养上调以及随后免疫炎症细胞向气道募 集的影响。我们尝试用特异性阻断抗体对神经生长因子进行免疫抑制，或用K252a对受体酪氨酸激酶进行化学抑制，以抑制淋巴细胞和单核细胞向受感染乳鼠气道的募集。在接受布地奈德、氟替卡松或赋形剂治疗的感染大鼠中研究了吸入性糖皮质激素的抗炎活性。对神经生长因子或其高亲和力受体酪氨酸激酶途径的免疫或化学抑制，抑制了受感染大鼠气道伤害性刺激引发的炎症细胞募集，从而降低了针对该病毒的局部和全身免疫炎症反应。吸入性糖皮质激素不影响受感染气道中的神经营养上调。因此，这些常用药物也无法阻止免疫和炎症效应细胞向受感染气道的募集。呼吸道合胞病毒感染气道中神经营养因子及其受体的过表达，对气道炎症和高反应性的发展至关重要，而气道炎症和高反应性对吸入性糖皮质激素的抗炎作用具有抗性。
