Farraj Aimen K, Haykal-Coates Najwa, Ledbetter Allen D, Evansky Paul A, Gavett Stephen H
Experimental Toxicology Division, U.S. EPA, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2006 Nov;94(1):183-92. doi: 10.1093/toxsci/kfl089. Epub 2006 Aug 23.
Neurotrophins, including nerve growth factor (NGF), partially mediate many features of allergic airways disease including airway hyperresponsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways responses in humans. We tested the hypothesis that DEP-induced enhancement of allergic airways disease in a murine model is dependent on normal function of the low affinity pan-neurotrophin receptor p75(NTR), or tyrosine kinase A (trkA), the primary receptor for NGF. Ovalbumin (OVA)-sensitized and nonallergic BALB/c mice were intranasally instilled with anti-p75(NTR), anti-trkA, or vehicle, 1 h before OVA aerosol challenge, and then exposed nose-only to the particulate matter fraction that was less than 2.5 microns in aerodynamic diameter fraction of Standard Reference Material 2975 DEP (2.0 mg/m(3)) or filtered air for 5 h. One day later, DEP-exposed OVA-allergic mice had significantly greater increases in ventilatory responses to methacholine (Mch), but not increased lung resistance, suggesting that the airflow changes may have originated in the nasal passages. DEP-exposed OVA-allergic mice also had increased lung IL-4 levels relative to all other groups. The instillation of anti-p75(NTR) or anti-trkA completely reversed the DEP-induced increases in ventilatory responses and lung IL-4 protein to levels similar to control mice. OVA-allergic DEP-exposed mice treated with anti-p75(NTR) had significantly less lung resistance in response to Mch relative to OVA-allergic DEP-exposed mice treated with anti-trkA. The results of this study demonstrate that the enhancement of allergic airways responses by DEP exposure is partly dependent on neurotrophins in mice. In addition, neurotrophins that bind p75(NTR), but not trkA, may mediate pulmonary central airways and tissue resistance responses to allergen and DEP exposure.
神经营养因子，包括神经生长因子（NGF），部分介导了过敏性气道疾病的许多特征，包括气道高反应性。与柴油燃烧相关的柴油废气颗粒（DEP）会加剧人类的许多此类过敏性气道反应。我们测试了这样一个假设，即DEP在小鼠模型中诱导的过敏性气道疾病增强依赖于低亲和力泛神经营养因子受体p75（NTR）或酪氨酸激酶A（trkA）（NGF的主要受体）的正常功能。在卵清蛋白（OVA）致敏和非过敏性BALB/c小鼠中，在OVA气雾剂激发前1小时经鼻内滴注抗p75（NTR）、抗trkA或赋形剂，然后仅让其鼻部暴露于标准参考物质2975 DEP（2.0 mg/m³）空气动力学直径小于2.5微米的颗粒物部分或过滤空气中5小时。一天后，暴露于DEP的OVA过敏性小鼠对乙酰甲胆碱（Mch）的通气反应显著增加，但肺阻力未增加，这表明气流变化可能起源于鼻道。与所有其他组相比，暴露于DEP的OVA过敏性小鼠肺IL-4水平也有所升高。滴注抗p75（NTR）或抗trkA可将DEP诱导的通气反应和肺IL-4蛋白增加完全逆转至与对照小鼠相似的水平。相对于用抗trkA处理的OVA过敏性DEP暴露小鼠，用抗p75（NTR）处理的OVA过敏性DEP暴露小鼠对Mch的肺阻力显著降低。本研究结果表明，DEP暴露增强过敏性气道反应在小鼠中部分依赖于神经营养因子。此外，结合p75（NTR）而非trkA的神经营养因子可能介导肺中央气道以及组织对过敏原和DEP暴露的阻力反应。
