Department of Physiological Sciences, University of Florida, Gainesville, FL, USA.
Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL, USA.
Physiol Rep. 2021 Feb;9(3):e14749. doi: 10.14814/phy2.14749.
Substance P (SP) is a tachykinin that regulates airway mucous secretion in both health and disease. Our study aimed to determine whether overexpression of SP without pre-existing inflammation was sufficient to induce changes in mucin secretion and transport in small airways. Utilizing porcine precision-cut lung slices, we measured the impact of AAV-mediated overexpression of SP on airway physiology ex vivo. Immunofluorescence signal intensity for MUC5AC was significantly increased in SP-overexpressed precision-cut lung slices compared to GFP controls. No difference in MUC5B signal intensity between treatments was detected. SP-overexpressed precision-cut lung slices also exhibited decreased IL10 mRNA, an important inhibitor of mucous cell metaplasia. Overt deficits in mucociliary transport were not noted, though a trend for decreased mean transport speed was detected in methacholine-challenged airways overexpressing SP compared to GFP controls. Pharmacologic inhibition of the NF-kβ pathway abrogated the effects of overexpression of SP on both MUC5AC and IL10. Collectively, these data suggest that overexpression of SP in the absence of existing inflammation increases MUC5AC via activation of the NF-kβ pathway. Thus, these data further highlight SP as a key driver of abnormal mucous secretion and underscore NF-kβ signaling as a pathway of potential therapeutic intervention.
P 物质（SP）是一种速激肽，可调节健康和疾病状态下的气道黏液分泌。我们的研究旨在确定 SP 的过表达是否足以在小气道中引起黏液分泌和转运的变化，而无需预先存在的炎症。我们利用猪的离体肺切片，测量了 AAV 介导的 SP 过表达对气道生理学的影响。与 GFP 对照相比，SP 过表达的离体肺切片中的 MUC5AC 的免疫荧光信号强度显著增加。在处理之间未检测到 MUC5B 信号强度的差异。SP 过表达的离体肺切片也表现出 IL10 mRNA 的减少，IL10 是黏液细胞化生的重要抑制剂。虽然在过表达 SP 的气道中，与 GFP 对照相比，在乙酰甲胆碱挑战下观察到黏液纤毛转运的平均转运速度略有降低，但未观察到明显的黏液纤毛转运缺陷。NF-kβ 通路的药理学抑制消除了 SP 过表达对 MUC5AC 和 IL10 的影响。综上所述，这些数据表明，在不存在现有炎症的情况下，SP 的过表达通过激活 NF-kβ 通路增加 MUC5AC。因此，这些数据进一步强调 SP 是异常黏液分泌的关键驱动因素，并强调 NF-kβ 信号通路作为潜在治疗干预的途径。
