Knudsen Lars, Atochina-Vasserman Elena N, Massa Christopher B, Birkelbach Bastian, Guo Chang-Jiang, Scott Pamela, Haenni Beat, Beers Michael F, Ochs Matthias, Gow Andrew J
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, Hannover, Germany;
Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania;
Am J Physiol Lung Cell Mol Physiol. 2015 Nov 1;309(9):L959-69. doi: 10.1152/ajplung.00017.2015. Epub 2015 Aug 28.
Surfactant protein D (SP-D) modulates the lung's immune system. Its absence leads to NOS2-independent alveolar lipoproteinosis and NOS2-dependent chronic inflammation, which is critical for early emphysematous remodeling. With aging, SP-D knockout mice develop an additional interstitial fibrotic component. We hypothesize that this age-related interstitial septal wall remodeling is mediated by NOS2. Using invasive pulmonary function testing such as the forced oscillation technique and quasistatic pressure-volume perturbation and design-based stereology, we compared 29-wk-old SP-D knockout (Sftpd(-/-)) mice, SP-D/NOS2 double-knockout (DiNOS) mice, and wild-type mice (WT). Structural changes, including alveolar epithelial surface area, distribution of septal wall thickness, and volumes of septal wall components (alveolar epithelium, interstitial tissue, and endothelium) were quantified. Twenty-nine-week-old Sftpd(-/-) mice had preserved lung mechanics at the organ level, whereas elastance was increased in DiNOS. Airspace enlargement and loss of surface area of alveolar epithelium coexist with increased septal wall thickness in Sftpd(-/-) mice. These changes were reduced in DiNOS, and compared with Sftpd(-/-) mice a decrease in volumes of interstitial tissue and alveolar epithelium was found. To understand the effects of lung pathology on measured lung mechanics, structural data were used to inform a computational model, simulating lung mechanics as a function of airspace derecruitment, septal wall destruction (loss of surface area), and septal wall thickening. In conclusion, NOS2 mediates remodeling of septal walls, resulting in deposition of interstitial tissue in Sftpd(-/-). Forward modeling linking structure and lung mechanics describes the complex mechanical properties by parenchymatous destruction (emphysema), interstitial remodeling (septal wall thickening), and altered recruitability of acinar airspaces.
表面活性蛋白D（SP-D）调节肺部免疫系统。缺乏SP-D会导致不依赖于一氧化氮合酶2（NOS2）的肺泡脂蛋白沉着症以及依赖于NOS2的慢性炎症，这对早期肺气肿重塑至关重要。随着年龄增长，SP-D基因敲除小鼠会出现额外的间质纤维化成分。我们推测这种与年龄相关的间质间隔壁重塑是由NOS2介导的。通过使用侵入性肺功能测试，如强迫振荡技术和准静态压力-容积扰动以及基于设计的体视学方法，我们比较了29周龄的SP-D基因敲除（Sftpd(-/-)）小鼠、SP-D/NOS2双基因敲除（DiNOS）小鼠和野生型小鼠（WT）。对包括肺泡上皮表面积、间隔壁厚度分布以及间隔壁成分（肺泡上皮、间质组织和内皮）体积等结构变化进行了量化。29周龄的Sftpd(-/-)小鼠在器官水平上保持了肺力学性能，而DiNOS小鼠的弹性增加。Sftpd(-/-)小鼠存在气腔扩大和肺泡上皮表面积减少，同时间隔壁厚度增加。这些变化在DiNOS小鼠中有所减轻，并且与Sftpd(-/-)小鼠相比，间质组织和肺泡上皮的体积有所减少。为了了解肺部病理对所测肺力学的影响，利用结构数据建立了一个计算模型，模拟肺力学作为气腔去募集、间隔壁破坏（表面积丧失）和间隔壁增厚的函数。总之，NOS2介导间隔壁重塑，导致Sftpd(-/-)小鼠间质组织沉积。将结构与肺力学联系起来的正向建模描述了由实质破坏（肺气肿）、间质重塑（间隔壁增厚）和腺泡气腔募集性改变所导致的复杂力学特性。
