Oliver Madavi N, Fabry Ben, Marinkovic Aleksandar, Mijailovich Srboljub M, Butler James P, Fredberg Jeffrey J
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
Am J Respir Cell Mol Biol. 2007 Sep;37(3):264-72. doi: 10.1165/rcmb.2006-0418OC. Epub 2007 Apr 26.
We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from sheep was attached to a servo-controller that applied a physiologic load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (P(L)), and fluctuations in P(L) associated with breathing. Starting at a reference length (L(ref)), ASM was stimulated with acetlycholine and held at constant P(L) of 4 cm H(2)O for 2 h. When all compartments were thickened to simulate the asthmatic airway but P(L) was held fixed, ASM shortened much more than that in the normal airway (to 0.52 L(ref) versus 0.66 L(ref)). When breathing with deep inspirations (DIs) was initiated, within the first three DIs the ASM in the normal airway lengthened to 0.84 L(ref), whereas that in the asthmatic airway remained stuck at 0.53 L(ref). Thickening of the smooth muscle layer alone produced the greatest muscle shortening (to 0.47 L(ref)) when compared with thickening of only submucosal (to 0.67 L(ref)) or only adventitial (to 0.62 L(ref)) compartments. With increased ASM mass, the ASM failed to lengthen in response to DIs, whereas in the airway with thickened submucosal and adventitial layers ASM lengthened dramatically (to 0.83 L(ref)). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this conclusion differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.
我们对气道壁重塑对气道平滑肌（ASM）缩短的影响进行了量化。从绵羊身上分离出的ASM附着在一个施加生理负荷的伺服控制器上。该负荷可以改变，以反映气道壁几何形状、弹性、实质组织束缚、跨肺压（P(L)）以及与呼吸相关的P(L)波动的特定变化。从参考长度（L(ref)）开始，用乙酰胆碱刺激ASM，并在4 cm H(2)O的恒定P(L)下保持2小时。当所有腔室都增厚以模拟哮喘气道，但P(L)保持固定时，ASM缩短的程度比正常气道大得多（分别为0.52 L(ref)和0.66 L(ref)）。当开始进行深呼吸（DI）呼吸时，在最初的三次DI内，正常气道中的ASM延长至0.84 L(ref)，而哮喘气道中的ASM仍停留在0.53 L(ref)。与仅黏膜下层（至0.67 L(ref)）或仅外膜层（至0.62 L(ref)）增厚相比，仅平滑肌层增厚导致的肌肉缩短最大（至0.47 L(ref)）。随着ASM质量增加，ASM无法对DI做出延长反应，而在黏膜下层和外膜层增厚的气道中，ASM显著延长（至0.83 L(ref)）。这些发现证实了长期以来的结论，即肌肉质量增加是功能上占主导地位的紊乱，但解释这一结论的机制与先前推测的有很大不同。此外，ASM质量增加解释了高反应性以及DI无法使哮喘气道舒张的原因。
