Pulmonary physiology and pathophysiology in isolated mouse lungs: Use of pressure-flow relationships to link pulmonary vascular function to pulmonary vascular mechanics and structure

To improve diagnosis and treatment of pulmonary hypertension, an important goal is to develop tools that provide information about structural changes in the vasculature from routine pressure and flow measurements. Using pulmonary vascular impedance (which includes both the steady and pulsatile hemodynamics) and numerical models of the pulmonary circulation, we investigated the mechanical/fluid dynamical relationships in the pulmonary vasculature in a healthy state and after exposure to chronic hypoxia, which causes pulmonary hypertension. In ex vivo mouse lungs, we showed the dependency of characteristic impedance (related to proximal arterial mechanics) ZC on mean pulmonary artery pressure (PAP) and the utility of this relationship to separate the proximal and distal effects of stimuli on the pulmonary circulation. We fit a theoretically-derived ZC-PAP relationship to experimental data to estimate stiffness, and initial diameter and wall thickness of proximal arteries. By combining these results with a structural analysis of the pulmonary arterial network from micro computed tomography images, we showed that chronic hypoxia causes both fixed and reactive changes in the distal vasculature and only fixed vascular changes in the proximal vasculature. We additionally investigated proximal and distal effects of chronic hypoxia in two transgenic strains of mice, one a model to investigate a potential molecular mechanism of pulmonary hypertension based on reduced bone morphogenetic protein receptors type 1a (Bmpr1a knockout) and the other a model deficient in the production of endothelial nitric oxide synthase (eNOS). Finally, we characterized the pressure-flow relationships in ex vivo mouse lungs given various combinations of flow waveforms, airway pressure and left atrial pressure. We investigated the mechanical/fluid dynamical mechanisms that govern these pressure-flow relationships using a global model of the pulmonary circulation that estimates peripheral pulmonary mechanics and a local model that models each generation to investigate possible changes in the circulation. The tools developed here for mouse lungs, including the ZC-PAP relationship and numerical models of the pulmonary circulation, provide important information about structural/mechanical as well as functional/hemodynamical changes in the lung with disease, which should improve our understanding of normal physiology and disease-inducing stimuli in mouse models of pulmonary vascular disease.