Mitchell Richard W, Dowell Maria L, Solway Julian, Lakser Oren J
Section of Pulmonary and Critical Care Medicine, University of Chicago, MC6026, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
Proc Am Thorac Soc. 2008 Jan 1;5(1):68-72. doi: 10.1513/pats.200705-058VS.
Superimposition of force fluctuations on contracted tracheal smooth muscle (TSM) has been used to simulate normal breathing. Breathing has been shown to reverse lung resistance of individuals without asthma and animals given methacholine to contract their airways; computed tomography scans also demonstrated bronchial dilation after a deep inhalation in normal volunteers. This reversal of airway resistance and bronchial constriction are absent (or much diminished) in individuals with asthma. Many studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening. Subsequent studies have shown that this force fluctuation-induced relengthening (FFIR) is a physiologically regulated phenomenon. We hypothesized that actin filament length in the smooth muscle of the airways regulates FFIR of contracted tissues. We based this hypothesis on the observations that bovine TSM strips contracted using acetylcholine (ACh) demonstrated amplitude-dependent FFIR that was sensitive to mitogen-activated protein kinase (p38 MAPK) inhibition- an upstream regulator of actin filament assembly. We demonstrated latrunculin B (sequesters actin monomers thus preventing their assimilation into filaments resulting in shorter filaments) greatly increases FFIR and jasplakinolide (an actin filament stabilizer) prevents the effects of latrunculin B incubation on strips of contracted canine TSM. We suspect that p38 MAPK inhibition and latrunculin B predispose to shorter actin filaments. These studies suggest that actin filament length may be a key determinant of airway smooth muscle relengthening and perhaps breathing-induced reversal of agonist-induced airway constriction.
将力的波动叠加在收缩的气管平滑肌（TSM）上已被用于模拟正常呼吸。研究表明，呼吸可逆转无哮喘个体以及给予乙酰甲胆碱使气道收缩的动物的肺阻力；计算机断层扫描也显示正常志愿者深吸气后支气管扩张。哮喘患者不存在（或大大减弱）气道阻力和支气管收缩的这种逆转情况。许多研究表明，将力振荡叠加在收缩的气道平滑肌上会导致平滑肌显著延长。随后的研究表明，这种力波动诱导的再延长（FFIR）是一种生理调节现象。我们假设气道平滑肌中的肌动蛋白丝长度调节收缩组织的FFIR。我们基于以下观察结果提出这一假设：使用乙酰胆碱（ACh）收缩的牛TSM条带表现出依赖振幅的FFIR，该FFIR对丝裂原活化蛋白激酶（p38 MAPK）抑制敏感——p38 MAPK是肌动蛋白丝组装的上游调节因子。我们证明了拉特罗毒素B（螯合肌动蛋白单体从而阻止其同化入丝，导致丝变短）极大地增加FFIR，而贾斯帕罗啉（一种肌动蛋白丝稳定剂）可防止拉特罗毒素B孵育对收缩的犬TSM条带产生影响。我们怀疑p38 MAPK抑制和拉特罗毒素B会导致肌动蛋白丝变短。这些研究表明，肌动蛋白丝长度可能是气道平滑肌再延长以及或许呼吸诱导的激动剂诱导的气道收缩逆转的关键决定因素。
