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首页> 外文期刊>PLoS Computational Biology >Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation
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Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation

机译：组织学和生化改变预测慢性肺炎症老化小鼠的肺部机械功能障碍

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Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.
机译：老化和慢性炎症既为呼吸兴奋地区的肺部产生复杂的结构和生化改变。表面活性剂蛋白D（SFTPD）缺乏的小鼠发育逐次相关的肺病理学，其特征在于组织破坏/重塑，泡沫巨噬细胞的积累和表面活性剂组合物的改变。本研究提出利用计算模型对正常老化和慢性炎症进行慢性炎症的组织结构的变化。从拟合简单的机械模型推断出血清和SFTPD - / - 小鼠的肺功能的改变，以呼吸阻抗数据（ZRS），然而，通过同时存在多个共存病理生理程序的解释已经混淆。与逆建模方法相比，该研究使用实验测量的模拟来重新承载老化和炎症改变Zrs。在8,27和80周龄（n = 8 /组）中，在C57BL6 / J小鼠和Congenic SFTPD - / - 小鼠中进行组织学和机械测量。开发了一种基于已发表的气道形态学的解剖学计算模型，并模拟0.5至20Hz之间的Zrs。从机械测量估算了气道口径和招募的终端呼气压力依赖性变化。使用粘弹性的恒定相模模拟组织元素。基于8周龄的野生型小鼠估计基线弹性分布，基于弹性纤维组合物，肺泡几何和表面活性剂组合物的实验测量改变，随机变化。对模型误差的称重减少，以增加模型复杂性，以确定机械病理学的基本特征及其对Zrs的贡献。使用最大似然方法，肺募集和减少弹性纤维密度的改变显示在气道开口的机械变化的预测，在更大程度上，比公开缩醛壁破坏。吞噬肺募集中的模型预测缺陷与肺衬里流体组合物无关，与年龄或基因型无关相关。

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