Zhang Xiao, Dash Ranjan K, Clough Anne V, Xie Dexuan, Jacobs Elizabeth R, Audi Said H
Department of Biomedical Engineering, Marquette University, Milwaukee, WI, United States.
Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Physiol. 2019 Mar 8;10:191. doi: 10.3389/fphys.2019.00191. eCollection 2019.
Altered lung tissue bioenergetics plays a key role in the pathogenesis of lung diseases. A wealth of information exists regarding the bioenergetic processes in mitochondria isolated from rat lungs, cultured pulmonary endothelial cells, and intact rat lungs under physiological and pathophysiological conditions. However, the interdependence of those processes makes it difficult to quantify the impact of a change in a single or multiple process(es) on overall lung tissue bioenergetics. Integrated computational modeling provides a mechanistic and quantitative framework for the bioenergetic data at different levels of biological organization. The objective of this study was to develop and validate an integrated computational model of lung bioenergetics using existing experimental data from isolated perfused rat lungs. The model expands our recently developed computational model of the bioenergetics of mitochondria isolated from rat lungs by accounting for glucose uptake and phosphorylation, glycolysis, and the pentose phosphate pathway. For the mitochondrial region of the model, values of kinetic parameters were fixed at those estimated in our recent model of the bioenergetics of mitochondria isolated from rat lungs. For the cytosolic region of the model, intrinsic parameters such as apparent Michaelis constants were determined based on previously published enzyme kinetics data, whereas extrinsic parameters such as maximal reaction and transport velocities were estimated by fitting the model solution to published data from isolated rat lungs. The model was then validated by assessing its ability to predict existing experimental data not used for parameter estimation, including relationships between lung nucleotides content, lung lactate production rate, and lung energy charge under different experimental conditions. In addition, the model was used to gain novel insights on how lung tissue glycolytic rate is regulated by exogenous substrates such as glucose and lactate, and assess differences in the bioenergetics of mitochondria isolated from lung tissue and those of mitochondria in intact lungs. To the best of our knowledge, this is the first model of lung tissue bioenergetics. The model provides a mechanistic and quantitative framework for integrating available lung tissue bioenergetics data, and for testing novel hypotheses regarding the role of different cytosolic and mitochondrial processes in lung tissue bioenergetics.
肺组织生物能量学的改变在肺部疾病的发病机制中起关键作用。关于从大鼠肺中分离出的线粒体、培养的肺内皮细胞以及生理和病理生理条件下完整大鼠肺中的生物能量过程，已有大量信息。然而，这些过程的相互依存性使得难以量化单个或多个过程的变化对整体肺组织生物能量学的影响。综合计算建模为不同生物组织水平的生物能量数据提供了一个机制性和定量性的框架。本研究的目的是利用来自离体灌注大鼠肺的现有实验数据，开发并验证一个肺生物能量学的综合计算模型。该模型通过考虑葡萄糖摄取和磷酸化、糖酵解以及磷酸戊糖途径，扩展了我们最近开发的从大鼠肺中分离出线粒体的生物能量学计算模型。对于模型的线粒体区域，动力学参数值固定为我们最近从大鼠肺中分离出线粒体的生物能量学模型中估计的值。对于模型的胞质区域，诸如表观米氏常数等内在参数是根据先前发表的酶动力学数据确定的，而诸如最大反应速度和转运速度等外在参数则通过将模型解与来自离体大鼠肺的已发表数据拟合来估计。然后通过评估其预测未用于参数估计的现有实验数据的能力来验证该模型，这些数据包括不同实验条件下肺核苷酸含量、肺乳酸产生率和肺能荷之间的关系。此外，该模型用于获得关于肺组织糖酵解速率如何受葡萄糖和乳酸等外源底物调节的新见解，并评估从肺组织分离出线粒体的生物能量学与完整肺中线粒体的生物能量学差异。据我们所知，这是第一个肺组织生物能量学模型。该模型为整合可用的肺组织生物能量学数据以及测试关于不同胞质和线粒体过程在肺组织生物能量学中作用的新假设提供了一个机制性和定量性的框架。
