Choe Melanie M, Sporn Peter H S, Swartz Melody A
Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, USA.
Am J Respir Cell Mol Biol. 2006 Sep;35(3):306-13. doi: 10.1165/rcmb.2005-0443OC. Epub 2006 Apr 6.
Airway wall remodeling is a hallmark of asthma, characterized by subepithelial thickening and extracellular matrix (ECM) remodeling. Mechanical stress due to hyperresponsive smooth muscle cells may contribute to this remodeling, but its relevance in a three-dimensional environment (where the ECM plays an important role in modulating stresses felt by cells) is unclear. To characterize the effects of dynamic compression in ECM remodeling in a physiologically relevant three-dimensional environment, a tissue-engineered human airway wall model with differentiated bronchial epithelial cells atop a collagen gel containing lung fibroblasts was used. Lateral compressive strain of 10 or 30% at 1 or 60 cycles per hour was applied using a novel straining device. ECM remodeling was assessed by immunohistochemistry and zymography. Dynamic strain, particularly at the lower magnitude, induced airway wall remodeling, as indicated by increased deposition of types III and IV collagen and increased secretion of matrix metalloproteinase-2 and -9. These changes paralleled increased myofibroblast differentiation and were fibroblast-dependent. Furthermore, the spatial pattern of type III collagen deposition correlated with that of myofibroblasts; both were concentrated near the epithelium and decreased diffusely away from the surface, indicating some epithelial control of the remodeling response. Thus, in a physiologically relevant three-dimensional model of the bronchial wall, dynamic compressive strain induced tissue remodeling that mimics many features of remodeling seen in asthma, in the absence of inflammation and dependent on epithelial-fibroblast signaling.
气道壁重塑是哮喘的一个标志，其特征是上皮下增厚和细胞外基质（ECM）重塑。高反应性平滑肌细胞产生的机械应力可能促成这种重塑，但其在三维环境（其中ECM在调节细胞感受到的应力方面起重要作用）中的相关性尚不清楚。为了在生理相关的三维环境中表征动态压缩对ECM重塑的影响，使用了一种组织工程化的人气道壁模型，在含有肺成纤维细胞的胶原凝胶上有分化的支气管上皮细胞。使用一种新型应变装置，以每小时1或60次循环施加10%或30%的横向压缩应变。通过免疫组织化学和酶谱法评估ECM重塑。动态应变，特别是较低幅度的应变，诱导了气道壁重塑，表现为III型和IV型胶原沉积增加以及基质金属蛋白酶-2和-9分泌增加。这些变化与肌成纤维细胞分化增加平行，且依赖于成纤维细胞。此外，III型胶原沉积的空间模式与肌成纤维细胞的模式相关；两者都集中在上皮附近，并从表面向远处扩散减少，表明上皮对重塑反应有一定的控制作用。因此，在支气管壁的生理相关三维模型中，动态压缩应变诱导了组织重塑，该重塑模拟了哮喘中所见重塑的许多特征，且不存在炎症并依赖上皮-成纤维细胞信号传导。
