Kelly Burrowes

Modeling RBC and Neutrophil Distribution Through an Anatomically Based Pulmonary Capillary Network

An anatomically based finite element model of the human pulmonary microcirculation has been created and applied to simulating regional variations in blood flow. A geometric mesh of the capillary network over the surface of a single alveolar sac is created using a Voronoi meshing technique. A pressure-flow relationship that describes blood cell transit is implemented in the network. Regional flow is investigated by imposing gravity-dependent transpulmonary and transmural boundary conditions. Comparisons of red and white blood cell transit times in the upper, mid, and lower lung showed physiologically consistent trends of a decreasing average transit time and an increased homogeneity of transit time distributions as a result of increasing average capillary diameter and flow down the height of a vertical lung. The model was found to reproduce experimentally consistent trends in red blood cell transit times and relative blood flows with respect to lung height. This model enables flow properties and cell transit time behavior in the pulmonary microcirculation under varying conditions, for example in different “zones” of the lung, to be explored.

Computational predictions of pulmonary blood flow gradients: Gravity versus structure

A computational model of blood flow through the human pulmonary arterial tree has been developed to investigate the mechanisms contributing to regional pulmonary perfusion in the isolated network when the lung is in different orientations. The arterial geometric model was constructed using a combination of computed tomography and a volume-filling branching algorithm. Equations governing conservation of mass, momentum, and vessel distension, incorporating gravity, were solved to predict pressure, flow, and vessel radius. Analysis of results in the upright posture, with and without gravity, and in the inverted, prone, and supine postures reveals significant flow heterogeneity and a persistent decrease in flow in the cranial and caudal regions for all postures suggesting that vascular geometry makes a major contribution to regional flow with gravity having a lesser role. Results in the isolated arterial tree demonstrate that the vascular path lengths and therefore the positioning of the pulmonary trunk relative to the rest of the network play a significant role in the determination of flow.

Towards a virtual lung: multi-scale, multi-physics modelling of the pulmonary system

The essential function of the lung, gas exchange, is dependent on adequate matching of ventilation and perfusion, where air and blood are delivered through complex branching systems exposed to regionally varying transpulmonary and transmural pressures. Structure and function in the lung are intimately related, yet computational models in pulmonary physiology usually simplify or neglect structure. The geometries of the airway and vascular systems and their interaction with parenchymal tissue have an important bearing on regional distributions of air and blood, and therefore on whole lung gas exchange, but this has not yet been addressed by modelling studies. Models for gas exchange have typically incorporated considerable detail at the level of chemical reactions, with little thought for the influence of structure. To date, relatively little attention has been paid to modelling at the cellular or subcellular level in the lung, or to linking information from the protein structure/interaction and cellular levels to the operation of the whole lung. We review previous work in developing anatomically based models of the lung, airways, parenchyma and pulmonary vasculature, and some functional studies in which these models have been used. Models for gas exchange at several spatial scales are briefly reviewed, and the challenges and benefits from modelling cellular function in the lung are discussed.

The interdependent contributions of gravitational and structural features to perfusion distribution in a multiscale model of the pulmonary circulation

Recent experimental and imaging studies suggest that the influence of gravity on the measured distribution of blood flow in the lung is largely through deformation of the parenchymal tissue. To study the contribution of hydrostatic effects to regional perfusion in the presence of tissue deformation, we have developed an anatomically structured computational model of the pulmonary circulation (arteries, capillaries, veins), coupled to a continuum model of tissue deformation, and including scale-appropriate fluid dynamics for blood flow in each vessel type. The model demonstrates that both structural and the multiple effects of gravity on the pulmonary circulation make a distinct contribution to the distribution of blood. It shows that postural differences in perfusion gradients can be explained by the combined effect of tissue deformation and extra-acinar blood vessel resistance to flow in the dependent tissue. However, gravitational perfusion gradients persist when the effect of tissue deformation is eliminated, highlighting the importance of the hydrostatic effects of gravity on blood distribution in the pulmonary circulation. Coupling of large- and small-scale models reveals variation in microcirculatory driving pressures within isogravitational planes due to extra-acinar vessel resistance. Variation in driving pressures is due to heterogeneous large-vessel resistance as a consequence of geometric asymmetry in the vascular trees and is amplified by the complex balance of pressures, distension, and flow at the microcirculatory level.

Blood flow redistribution and ventilation-perfusion mismatch during embolic pulmonary arterial occlusion

Acute pulmonary embolism causes redistribution of blood in the lung, which impairs ventilation/perfusion matching and gas exchange and can elevate pulmonary arterial pressure (PAP) by increasing pulmonary vascular resistance (PVR). An anatomically-based multi-scale model of the human pulmonary circulation was used to simulate pre- and post-occlusion flow, to study blood flow redistribution in the presence of an embolus, and to evaluate whether reduction in perfused vascular bed is sufficient to increase PAP to hypertensive levels, or whether other vasoconstrictive mechanisms are necessary. A model of oxygen transfer from air to blood was included to assess the impact of vascular occlusion on oxygen exchange. Emboli of 5, 7, and 10 mm radius were introduced to occlude increasing proportions of the vasculature. Blood flow redistribution was calculated after arterial occlusion, giving predictions of PAP, PVR, flow redistribution, and micro-circulatory flow dynamics. Because of the large flow reserve capacity (via both capillary recruitment and distension), approximately 55% of the vasculature was occluded before PAP reached clinically significant levels indicative of hypertension. In contrast, model predictions showed that even relatively low levels of occlusion could cause localized oxygen deficit. Flow preferentially redistributed to gravitationally non-dependent regions regardless of occlusion location, due to the greater potential for capillary recruitment in this region. Red blood cell transit times decreased below the minimum time for oxygen saturation (<0.25 s) and capillary pressures became high enough to initiate cell damage (which may result in edema) only after ~80% of the lung was occluded.

Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM)

The respiratory system comprises several scales of biological complexity: the genes, cells and tissues that work in concert to generate resultant function. Malfunctions of the structure or function of components at any spatial scale can result in diseases, to the detriment of gas exchange, right heart function and patient quality of life. Vast amounts of data emerge from studies across each of the biological scales; however, the question remains: how can we integrate and interpret these data in a meaningful way? Respiratory disease presents a huge health and economic burden, with the diseases asthma and chronic obstructive pulmonary disease (COPD) affecting over 500 million people worldwide. Current therapies are inadequate owing to our incomplete understanding of the disease pathophysiology and our lack of recognition of the enormous disease heterogeneity: we need to characterize this heterogeneity on a patient-specific basis to advance healthcare. In an effort to achieve this goal, the AirPROM consortium (Airway disease Predicting Outcomes through patient-specific computational Modelling) brings together a multi-disciplinary team and a wealth of clinical data. Together we are developing an integrated multi-scale model of the airways in order to unravel the complex pathophysiological mechanisms occurring in the diseases asthma and COPD.

Systems Medicine: from molecular features and models to the clinic in COPD

Background and hypothesisChronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.Objective and methodOur overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework.ResultsIn the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.ConclusionsThe results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.

Species−specific pulmonary arterial asymmetry determines species differences in regional pulmonary perfusion

The functional significance of differences in pulmonary vascular branching and diameter asymmetry between the human and quadruped lung has not previously been addressed. To evaluate the contribution of branching asymmetry to observable species differences in blood flow gradients, computed distributions of blood flow were compared in structure-based models of the human and ovine pulmonary arteries. The models were derived using a combination of computed tomography and a volume-filling algorithm. Pressure, flow, and deformed vessel diameter were calculated in both species models using equations representing conservation of mass and momentum, and a pressure–diameter relationship. The major difference between the human and ovine results was the presence of a large region of “zone 4” flow and higher mean flows in the central region of the ovine lung compared to that in the human. Heterogeneity in tissue perfusion and the contribution of gravity were similar in both species models; however, the gravitationally directed gradients of perfusion in the human and ovine models were different and each consistent with human and quadruped measurements, respectively. The results suggest that measured species differences in pulmonary perfusion gradients are largely determined by differences in branching asymmetry.

Computational modeling of the obstructive lung diseases asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway obstruction and airflow limitation and pose a huge burden to society. These obstructive lung diseases impact the lung physiology across multiple biological scales. Environmental stimuli are introduced via inhalation at the organ scale, and consequently impact upon the tissue, cellular and sub-cellular scale by triggering signaling pathways. These changes are propagated upwards to the organ level again and vice versa. In order to understand the pathophysiology behind these diseases we need to integrate and understand changes occurring across these scales and this is the driving force for multiscale computational modeling.There is an urgent need for improved diagnosis and assessment of obstructive lung diseases. Standard clinical measures are based on global function tests which ignore the highly heterogeneous regional changes that are characteristic of obstructive lung disease pathophysiology. Advances in scanning technology such as hyperpolarized gas MRI has led to new regional measurements of ventilation, perfusion and gas diffusion in the lungs, while new image processing techniques allow these measures to be combined with information from structural imaging such as Computed Tomography (CT). However, it is not yet known how to derive clinical measures for obstructive diseases from this wealth of new data. Computational modeling offers a powerful approach for investigating this relationship between imaging measurements and disease severity, and understanding the effects of different disease subtypes, which is key to developing improved diagnostic methods.Gaining an understanding of a system as complex as the respiratory system is difficult if not impossible via experimental methods alone. Computational models offer a complementary method to unravel the structure-function relationships occurring within a multiscale, multiphysics system such as this. Here we review the current state-of-the-art in techniques developed for pulmonary image analysis, development of structural models of the respiratory system and predictions of function within these models. We discuss application of modeling techniques to obstructive lung diseases, namely asthma and emphysema and the use of models to predict response to therapy. Finally we introduce a large European project, AirPROM that is developing multiscale models to investigate structure-function relationships in asthma and COPD.

Pulmonary embolism: predicting disease severity

Pulmonary embolism (PE) is the most common cause of acute pulmonary hypertension, yet it is commonly undiagnosed, with risk of death if not recognized promptly and managed accordingly. Patients typically present with hypoxemia and hypocapnia, although the presentation varies greatly, being confounded by co-mordidities such as pre-existing cardio-respiratory disease. Previous studies have demonstrated variable patient outcomes in spite of similar extent and distribution of pulmonary vascular occlusion, but the pathophysiological determinants of outcome remain unclear. Computational models enable exact control over many of the compounding factors leading to functional outcomes and therefore provide a useful tool to understand and assess these mechanisms. We review the current state of pulmonary blood flow models. We present a pilot study within 10 patients presenting with acute PE, where patient-derived vascular occlusions are imposed onto an existing model of the pulmonary circulation enabling predictions of resultant haemodynamics after embolus occlusion. Results show that mechanical obstruction alone is not sufficient to cause pulmonary arterial hypertension, even when up to 65 per cent of lung tissue is occluded. Blood flow is found to preferentially redistribute to the gravitationally non-dependent regions. The presence of an additional downstream occlusion is found to significantly increase pressures.