Department of Physiology, University of Massachusetts Medical School, Worcester, 01655, USA.
Am J Respir Cell Mol Biol. 2010 Aug;43(2):179-91. doi: 10.1165/rcmb.2009-0222OC. Epub 2009 Sep 18.
The etiology of airway hyperresponsiveness associated with asthma requires an understanding of the regulatory mechanisms mediating human airway smooth muscle cell (SMC) contraction. The objective of this study was to determine how human airway SMC contraction (induced by histamine) and relaxation (induced by formoterol) are regulated by Ca(2+) oscillations and Ca(2+) sensitivity. The responses of human small airways and their associated SMCs were studied in human lung slices cut from agarose-inflated lungs. Airway contraction was measured with phase-contrast video microscopy. Ca(2+) signaling and Ca(2+) sensitivity of airway SMCs were measured with two-photon fluorescence microscopy and Ca(2+)-permeabilized lung slices. The agonist histamine induced contraction of human small airways by stimulating both an increase in intracellular Ca(2+) concentration in the SMCs in the form of oscillatory Ca(2+) waves and an increase in Ca(2+) sensitivity. The frequency of the Ca(2+) oscillations increased with histamine concentration, and correlated with increased contraction. Formoterol induced airway relaxation at low concentrations by initially decreasing SMC Ca(2+) sensitivity. At higher concentrations, formoterol additionally slowed or inhibited the Ca(2+) oscillations of the SMCs to relax the airways. The action of formoterol was only slowly reversed. Human lung slices provide a powerful experimental assay for the investigation of small airway physiology and pharmacology. Histamine induces contraction by simultaneously increasing SMC Ca(2+) signaling and Ca(2+) sensitivity. Formoterol induces long-lasting relaxation by initially reducing the Ca(2+) sensitivity and, subsequently, the frequency of the Ca(2+) oscillations of the airway SMCs.
气道高反应性与哮喘的病因需要了解调节人类气道平滑肌细胞（SMC）收缩的机制。本研究的目的是确定人类气道 SMC 收缩（由组胺诱导）和舒张（由福莫特罗诱导）是如何被 Ca(2+) 振荡和 Ca(2+) 敏感性调节的。通过在琼脂糖充气肺中切割的人肺切片研究了小气道及其相关 SMC 的反应。通过相差视频显微镜测量气道收缩。通过双光子荧光显微镜和 Ca(2+)-通透肺切片测量气道 SMC 的 Ca(2+) 信号和 Ca(2+) 敏感性。激动剂组胺通过刺激 SMC 内的 Ca(2+) 浓度以振荡 Ca(2+) 波的形式增加，以及增加 Ca(2+) 敏感性，从而引起人类小气道的收缩。Ca(2+) 振荡的频率随组胺浓度的增加而增加，并与收缩增加相关。福莫特罗在低浓度时通过最初降低 SMC Ca(2+) 敏感性诱导气道舒张。在较高浓度时，福莫特罗还会减缓或抑制 SMC 的 Ca(2+) 振荡，以松弛气道。福莫特罗的作用仅缓慢逆转。人肺切片为研究小气道生理学和药理学提供了强大的实验测定方法。组胺通过同时增加 SMC Ca(2+) 信号和 Ca(2+) 敏感性来诱导收缩。福莫特罗通过最初降低 Ca(2+) 敏感性并随后降低气道 SMC 的 Ca(2+) 振荡频率来诱导长时间的舒张。
