Strategies for the Physiome

A mathematical model aids in describing the physical processes and behavior of a system using mathematical equations; often in a simplified manner. A number of experiments implement simple mathematical models in an attempt to catalogue and explain the behavior of a system. However, these models are typically limited to a specific area of the entire system response. In recent years, efforts have been made on the ‘Physiome Project’, which led to the development of more comprehensive models of biological processes. These processes cover a wide range of studies, comprising from ‘subcellular organelles’ to ‘whole organisms’. The main goal of the ‘Physiome Project’ is to use computational modeling to analyze integrative biological function. This process is achieved by developing a simulation system for hypothesis testing. Currently, an extensive development of cardiovascular, endocrine and nervous system models has been achieved. The overall objective of this thesis is to contribute to the ‘Physiome Project’ by demonstrating a comprehensive integrative model of the pulmonary circulation.

The function of pulmonary circulation is to carry oxygen depleted blood away from the heart to the lungs through the pulmonary arteries. The blood gets oxygenated in the lungs and is sent back to the heart through the pulmonary veins. Inside of the lungs, the main pulmonary artery are divided into smaller arteries which are further subdivided into smaller arterioles over a number of generations.The arterioles have strong muscular walls, which allow them to constrict or dilate, corresponding with the O₂/C0₂ levels in blood. The final generation of arterioles is emptied into the capillary sheet, where the exchange of gases occurs .The oxygenation takes place between blood and airways (alveoli) through the process of diffusion. The venules collect blood from the capillaries and merge into pulmonary veins. Pulmonary veins transport the oxygenated blood to the left ventricle before passing through the left atrium. Once the oxygenated blood reaches the left ventricle it can be distributed to various organs and tissues via the systemic circulation.

 Haworth has already developed a large scale model of a dog’s pulmonary circulation. Their research was based on the fundamental physical laws governing fluid dynamics and integrated extant experimental data from the literature. This project will aim to extend the work of Haworth et al (1991) to develop a pulmonary circulation model of a rat with a user friendly interface and perform hypothesis driven simulations. Furthermore, the study will seek to investigate the factors that lead to pulmonary arterial hypertension as a result of exposure to chronic hypoxia in rats.

In the recent past, pulmonary arterial hypertension has been increasingly identified as a significant public health problem. It is characterized by pulmonary vascular remodeling, i.e. change in the structural and biomechanical architecture of the pulmonary vessels. Pulmonary arterial hypertension is also associated with persistent vasoconstriction, narrowing blood vessels and medial smooth muscle thickening of the pulmonary arteries. These processes can lead to an increased pulmonary artery pressure and vascular resistance, which will cause a right-sided heart failure.

Chronic hypoxia is often used as an experimental stimulus for invoking pulmonary hypertension and vascular remodeling in rats. Researchers have set forth several hypotheses to explain the biological factors responsible for hemodynamic impact of pulmonary vascular remodeling on chronic hypoxia. One of the most popular hypothesis is that decreased distensibilty of the pulmonary arterial vessels can be caused by long term exposure to hypoxia. This can also account for an increase in the pulmonary arterial pressure. However, other researchers have suggested that vascular structural changes such as loss of small blood vessels (rarefaction) are primarily responsible for an increase in pressure.

The rat’s pulmonary circulation model will evaluate these hypotheses to form an understanding of the factors responsible for an increased pulmonary arterial pressure with exposure to chronic hypoxia.