Activation of TRPV4 Regulates Respiration through Indirect Activation of Bronchopulmonary Sensory Neurons.
Activation of TRPV4 Regulates Respiration through Indirect Activation of Bronchopulmonary Sensory Neurons.
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DOI：
10.3389/fphys.2016.00065
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发表时间：
2016
影响因子：
4
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Gu QD;Moss CR 2nd;Kettelhut KL;Gilbert CA;Hu H
瞬时受体电位香草素受体4（TRPV 4）是一种钙渗透性非选择性阳离子通道，与许多生理和病理功能有关。本研究旨在研究TRPV 4激活对呼吸的影响，并探讨支气管肺感觉神经元的可能参与。将TRPV 4激动剂GSK 1016790 A注入麻醉的自主呼吸大鼠右心房，观察呼吸变化。采用膜片钳技术观察GSK 1016790 A和TRPV 4激动剂4α-PDD对培养的大鼠迷走神经支气管感觉神经元的作用。进行免疫组织化学以确定从TRPV 4-EGFP小鼠获得的肺切片中表达TRPV 4的细胞。我们的结果表明，右心房注射GSK 1016790 A在麻醉大鼠中诱发了缓慢发展的、持续时间长的浅快呼吸。TRPV 4的激活也显著增强辣椒素诱发的化学反射反应。由GSK 1016790 A诱导的通气改变被两条迷走神经的切割或神经周辣椒素处理所消除，表明支气管肺传入神经元的参与。选择性TRPV 4拮抗剂GSK 2193874和吲哚美辛抑制环氧合酶可消除GSK 1016790 A的刺激和致敏作用。令人惊讶的是，GSK 1016790 A或4α-PDD既不激活分离的支气管肺感觉神经元，也不调节这些神经元中辣椒素诱导的内向电流。此外，在肺泡巨噬细胞、肺泡上皮细胞和血管内皮细胞中发现TRPV 4表达。总的来说，我们的研究结果表明，GSK 1016790 A通过间接激活支气管感觉神经元来调节呼吸，可能是通过刺激肺和气道中的其他TRPV 4表达细胞。
Transient receptor potential vanilloid receptor 4 (TRPV4) is a calcium-permeable non-selective cation channel implicated in numerous physiological and pathological functions. This study aimed to investigate the effect of TRPV4 activation on respiration and to explore the potential involvement of bronchopulmonary sensory neurons. Potent TRPV4 agonist GSK1016790A was injected into right atrium in anesthetized spontaneously breathing rats and the changes in breathing were measured. Patch-clamp recording was performed to investigate the effect of GSK1016790A or another TRPV4 activator 4α-PDD on cultured rat vagal bronchopulmonary sensory neurons. Immunohistochemistry was carried out to determine the TRPV4-expressing cells in lung slices obtained from TRPV4-EGFP mice. Our results showed, that right-atrial injection of GSK1016790A evoked a slow-developing, long-lasting rapid shallow breathing in anesthetized rats. Activation of TRPV4 also significantly potentiated capsaicin-evoked chemoreflex responses. The alteration in ventilation induced by GSK1016790A was abolished by cutting or perineural capsaicin treatment of both vagi, indicating the involvement of bronchopulmonary afferent neurons. The stimulating and sensitizing effects of GSK1016790A were abolished by a selective TRPV4 antagonist GSK2193874 and also by inhibiting cyclooxygenase with indomethacin. Surprising, GSK1016790A or 4α-PDD did not activate isolated bronchopulmonary sensory neurons, nor did they modulate capsaicin-induced inward currents in these neurons. Furthermore, TRPV4 expression was found in alveolar macrophages, alveolar epithelial, and vascular endothelial cells. Collectively, our results suggest that GSK1016790A regulates the respiration through an indirect activation of bronchopulmonary sensory neurons, likely via its stimulation of other TRPV4-expressing cells in the lungs and airways.