Neurokinin-neurotrophin interactions in airway smooth muscle

作者：Meuchel Lucas W; Stewart Alecia; Smelter Dan F; Abcejo Amard J; Thompson Michael A; Zaidi Syed I A; Martin Richard J; Prakash Y S^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2011, 301(1): L91-L98.

DOI：10.1152/ajplung.00320.2010

• bronchial smooth muscle
• oxygen
• hyperoxia
• brain-derived neurotrophic factor
• tropomyosin related kinase
• calcium
• substance P

Meuchel LW, Stewart A, Smelter DF, Abcejo AJ, Thompson MA, Zaidi SI, Martin RJ, Prakash YS. Neurokinin-neurotrophin interactions in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 301: L91-L98, 2011. First published April 22, 2011; doi: 10.1152/ajplung.00320.2010.-Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brain-derived neurotrophic factor (BDNF; potentially derived from nerves as well as airway smooth muscle; ASM) and its tropomyosin-related kinase receptor, TrkB, are involved in enhanced airway contractility. In this study, we hypothesized that neurokinins and neurotrophins are linked in enhancing intracellular Ca(2+) concentration ([Ca(2+)](i)) regulation in ASM. In rat ASM cells, 24 h exposure to 10 nM SP significantly increased BDNF and TrkB expression (P < 0.05). Furthermore, [Ca(2+)](i) responses to 1 mu M ACh as well as BDNF (30 min) effects on [Ca(2+)](i) regulation were enhanced by prior SP exposure, largely via increased Ca(2+) influx (P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 mu M, P < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-F(c); 1 mu g/ml), as well as tyrosine kinase inhibition (100 nM K252a), substantially blunted SP effects (P < 0.05). Overnight (24 h) exposure of ASM cells to 50% oxygen increased BDNF and TrkB expression and potentiated both SP- and BDNF-induced enhancement of [Ca(2+)](i) (P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonist-induced [Ca(2+)](i) regulation in ASM. The autocrine mechanism we present here represents a new area in the development of bronchoconstrictive reflex response and airway hyperreactive disorders.

• 出版日期2011-7