Piedimonte G, Pickles R J, Lehmann J R, McCarty D, Costa D L, Boucher R C
Department of Pediatrics, University of Miami School of Medicine, Florida, USA.
Am J Respir Cell Mol Biol. 1997 Mar;16(3):250-8. doi: 10.1165/ajrcmb.16.3.9070609.
Human trials for the treatment of cystic fibrosis lung disease with adenoviral vectors have been complicated by acute inflammatory reactions of unknown etiology. Because replicating respiratory viruses can potentiate tachykinin-mediated neurogenic inflammatory responses in airways, we studied whether the endotracheal administration of a replication-deficient adenoviral vector potentiated this response. The vector Ad5CMVLacZ was administered endotracheally to rats and the leakage of Evans blue dye was used to measure the capsaicin-induced neurogenic albumin extravasation. These studies show that neurogenic albumin extravasation is significantly potentiated in the airways of rats after administration of Ad5CMVLacZ. This inflammatory response can be blocked by selective antagonists of the substance P receptor or by glucocorticoids. Therefore, (1) the acute airway inflammation observed in patients after exposure to adenoviral vectors may exhibit a neurogenic component, which can be blocked pharmacologically, and (2) preclinical adenoviral vector safety studies of other organs innervated by the tachykinin system, e.g., coronary arteries and gastrointestinal tract, should include assessment of neurogenic inflammation.
用腺病毒载体治疗囊性纤维化肺病的人体试验因不明病因的急性炎症反应而变得复杂。由于复制性呼吸道病毒可增强气道中速激肽介导的神经源性炎症反应，我们研究了气管内给予复制缺陷型腺病毒载体是否会增强这种反应。将载体Ad5CMVLacZ经气管内给予大鼠，并使用伊文思蓝染料渗漏来测量辣椒素诱导的神经源性白蛋白外渗。这些研究表明，给予Ad5CMVLacZ后，大鼠气道中的神经源性白蛋白外渗显著增强。这种炎症反应可被P物质受体的选择性拮抗剂或糖皮质激素阻断。因此，（1）接触腺病毒载体后患者中观察到的急性气道炎症可能表现出神经源性成分，可通过药物阻断，（2）对速激肽系统支配的其他器官（如冠状动脉和胃肠道）进行腺病毒载体临床前安全性研究时，应包括对神经源性炎症的评估。
