A Large-Scale Mathematical Model of the Rat Pulmonary Circulation and the Effect of Chronic Hypoxia

Mathematical models are useful for developing understanding of the behavior of complex biological systems. Recent work on a “physiome” project is aimed at using computational modeling to analyze integrative biological function by developing a simulation system for hypothesis testing (Borg & Hunter, 2003). To date, extensive work on cardiovascular, endocrine and nervous system models has been undertaken. Our objective here is to contribute to this effort by further developing a comprehensive integrative model of the pulmonary circulation. A computational model of the dog pulmonary circulation was originally developed by Haworth et al. (Haworth S. T., 1996; Haworth, Linehan, Bronikowski, & Dawson, 1991). In this thesis, their work was extended to the rat pulmonary circulation. The rat model geometry is characterized by 18 orders of arteries and 19 orders of veins. The average distensibility (% increase in diameter over the undistended diameter) for the model arteries and veins are 2.8 %/mmHg and 1.6 %/mmHg. These arterial and venous trees are connected by a capillary sheet with an area of 0.123 cm2. The model was validated and the calculated pressures, arterial-capillary-venous resistances, volumes, and compliances of the model agree well with the experimental estimates in the rat lung under zone 3 conditions. The model was used to evaluate the common structural hallmarks of pulmonary vascular remodeling as a result of exposure to chronic hypoxia (low inspired oxygen levels), such as the decrease in arterial and venous distensibility, reduction in capillary surface area and reduction in the number of small arteries. Our results show that these factors are not alone sufficient to account for the reported increase in pulmonary arterial pressure in response to chronic hypoxia induced pulmonary hypertension. This extended model provides a graphical user interface for choosing parameters, simulation models, and numerical options for performing either steady state or dynamic simulations, and for displaying model simulation results. The results of this study demonstrate the potential utility of this model for furthering the understanding of the underling mechanisms of pulmonary hypertension, and the effects of other lung disorders on the pulmonary circulation