Young Sarah Marie, Liu Sheng, Joshi Rashika, Batie Matthew R, Kofron Matthew, Guo Jinbang, Woods Jason C, Varisco Brian Michael
College of Veterinary Medicine, The Ohio State University, Columbus, Ohio;
Division of Critical Care Medicine, Cincinnati Children's Hospital, Cincinnati, Ohio; Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio.
J Appl Physiol (1985). 2015 Apr 1;118(7):921-31. doi: 10.1152/japplphysiol.00954.2014. Epub 2015 Jan 22.
Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse. Remodeling was restricted to alveolar walls and ducts and was nearly absent in dense elastin band structures. In the mouse pneumonectomy model of compensatory lung growth, elastase activity increased threefold, peaking at 14 days postpneumonectomy and was higher in the accessory lobe compared with other lobes. Remodeling during normal development and during compensatory lung growth was different with increased major airway and pulmonary arterial remodeling during development but not regeneration, and with homogenous remodeling throughout the parenchyma during development, but increased remodeling only in subpleural regions during compensatory lung growth. Left lung wax plombage prevented increased lung elastin during compensatory lung growth. To test whether the adult lung retains an innate capacity to remodel elastin, we developed a confocal microscope-compatible stretching device. In ex vivo adult mouse lung sections, lung elastase activity increased exponentially with strain and in peripheral regions of lung more than in central regions. Our study demonstrates that lung elastase activity is stretch-dependent and supports a model in which externally applied forces influence the composition, structure, and function of the matrix during periods of alveolar septation.
肺基质的合成与重塑对于肺的原发性生长和代偿性生长都是必要的。由于在呼吸周期中发育中的肺组织会受到周期性的负压作用，我们推测拉伸是肺基质重塑的关键调节因子。通过对全肺和全叶弹性蛋白酶原位酶谱图像进行定量图像分析，我们发现小鼠出生后肺形态发生的肺泡期弹性蛋白酶活性增加了两倍。重塑仅限于肺泡壁和肺泡管，在致密弹性蛋白带结构中几乎不存在。在代偿性肺生长的小鼠肺叶切除模型中，弹性蛋白酶活性增加了三倍，在肺叶切除后14天达到峰值，且副叶中的活性高于其他叶。正常发育和代偿性肺生长过程中的重塑有所不同，发育过程中主气道和肺动脉重塑增加，而再生过程中则不然；发育过程中整个实质内的重塑是均匀的，但代偿性肺生长过程中仅胸膜下区域的重塑增加。左肺蜡填充可防止代偿性肺生长期间肺弹性蛋白增加。为了测试成年肺是否保留重塑弹性蛋白的内在能力，我们开发了一种与共聚焦显微镜兼容的拉伸装置。在离体成年小鼠肺切片中，肺弹性蛋白酶活性随应变呈指数增加，且肺外周区域的增加幅度大于中央区域。我们的研究表明，肺弹性蛋白酶活性依赖于拉伸，并支持一种模型，即在肺泡间隔形成期间，外部施加的力会影响基质的组成、结构和功能。
