Helyes Zsuzsanna, Elekes Krisztián, Németh József, Pozsgai Gábor, Sándor Katalin, Kereskai László, Börzsei Rita, Pintér Erika, Szabó Arpád, Szolcsányi János
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.
Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1173-81. doi: 10.1152/ajplung.00406.2006. Epub 2007 Jan 19.
Airways are densely innervated by capsaicin-sensitive sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) receptors/ion channels, which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The aim of the present study was to investigate the role of TRPV1 receptors in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological, and biochemical techniques using receptor gene-deficient mice. Inflammation was evoked by intranasal administration of Escherichia coli lipopolysaccharide (60 microl, 167 microg/ml) in TRPV1 knockout (TRPV1(-/-)) mice and their wild-type counterparts (TRPV1(+/+)) 24 h before measurement. Airway reactivity was assessed by unrestrained whole body plethysmography, and its quantitative indicator, enhanced pause (Penh), was calculated after inhalation of the bronchoconstrictor carbachol. Histological examination and spectrophotometric myeloperoxidase measurement was performed from the lung. Somatostatin concentration was measured in the lung and plasma with radioimmunoassay. Bronchial hyperreactivity, histological lesions (perivascular/peribronchial edema, neutrophil/macrophage infiltration, goblet cell hyperplasia), and myeloperoxidase activity were significantly greater in TRPV(-/-) mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1(+/+) but not TRPV1(-/-) animals. In TRPV1(-/-) mice, exogenous administration of somatostatin-14 (4 x 100 microg/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wild-type mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 x 250 microg/kg ip) increased these parameters. This study provides the first evidence for a novel counterregulatory mechanism during endotoxin-induced airway inflammation, which is mediated by somatostatin released from sensory nerve terminals in response to activation of TRPV1 receptors of the lung. It reaches the systemic circulation and inhibits inflammation and consequent bronchial hyperreactivity.
气道由表达瞬时受体电位香草酸亚型1（TRPV1）受体/离子通道的辣椒素敏感感觉神经元密集支配，这些受体/离子通道通过释放感觉神经肽在炎症过程中发挥重要调节作用。本研究的目的是使用受体基因缺陷小鼠，通过功能、形态学和生化技术研究TRPV1受体在内毒素诱导的气道炎症及随后的支气管高反应性中的作用。在测量前24小时，通过鼻内给予大肠杆菌脂多糖（60微升，167微克/毫升）在TRPV1基因敲除（TRPV1(-/-)）小鼠及其野生型对照（TRPV1(+/+)）中诱发炎症。通过无束缚全身体积描记法评估气道反应性，并在吸入支气管收缩剂卡巴胆碱后计算其定量指标增强暂停（Penh）。对肺进行组织学检查和分光光度法髓过氧化物酶测量。用放射免疫测定法测量肺和血浆中的生长抑素浓度。TRPV(-/-)小鼠的支气管高反应性、组织学病变（血管周围/支气管周围水肿、中性粒细胞/巨噬细胞浸润、杯状细胞增生）和髓过氧化物酶活性明显更高。炎症使TRPV1(+/+)动物的肺和血浆生长抑素浓度显著升高，但TRPV1(-/-)动物未升高。在TRPV1(-/-)小鼠中，外源性给予生长抑素-14（4×100微克/千克腹腔注射）可减轻炎症和高反应性。此外，在野生型小鼠中，用环孢生长抑素（4×250微克/千克腹腔注射）拮抗生长抑素受体可增加这些参数。本研究首次证明了内毒素诱导的气道炎症过程中一种新的负调节机制，该机制由肺TRPV1受体激活后感觉神经末梢释放的生长抑素介导。它进入体循环并抑制炎症及随后的支气管高反应性。
