Pulmonary Capillary Network Research Articles

A model of perfusion of the healthy human lung

This study presents a model that simulates the pulmonary capillary perfusion. The model describes the lungs as divided into horizontal layers and includes: capillary geometry; capillary wall elasticity; pressure at the pulmonary artery; blood viscosity; the effect of the chest wall; the change in lung height and hydrostatic effects of the lung tissue and of the blood during breathing. The model simulates pulsatile blood perfusion with an increasing blood distribution down the lungs, in agreement with previous experimental studies. Moreover the model is in agreement with experimentally measured total capillary perfusion, total capillary volume, total capillary surface area and transition time of red blood cells passing through the pulmonary capillary network. The presented model is the first to be validated against the mentioned experimental data and to model the link between airway pressure, lung volume and perfusion.

Contact time of red blood cells with alveolar air

The contact time between red blood cells and alveolar air is one of the most important factors affecting red blood cell oxygenation in the lungs. Many methods have been presented for contact time measurement, however, no work, evaluating it by tracing red blood cell movement through the pulmonary capillary network has been reported. In this study, the contact time was measured by tracing red blood cells, stained with fluorescein isothiocyanate (FITC-RBC), with a fluorescent microscope in living rat lung. It was assumed that the transit time of red blood cells through the pulmonary capillary network was equivalent to the contact time. The flow patterns of red blood cells were complicated, namely, FITC-RBC discharged from one arteriole flowed into several venules through many routes in the pulmonary capillary network, and those ejected from several arterioles pored into one venule. Furthermore, the FITC-RBC flow rate changed many times in the pulmonary capillary network. The contact time varied from 0 to 1.2 seconds. The measurement was performed in each classified route by the straight distance between arteriole and venule, in order to simplify the various capillary networks. The results revealed that the contact time was 0.3, 0.4, 0.5, 0.7, 0.7 and 0.7 seconds on the average respectively in the routes of 101--150, 151--200, 201--250, 251--300 and 301--350 microns straight distance. The frequencies of the above distance routes were 5, 8, 15, 23, 26 and 21%, respectively. As a result, the total lung contact time calculated using these frequencies was 0.7 +/- 0.2 seconds (mean +/- standard deviation) on average.

A Mathematical Physiological Model of the Pulmonary Capillary Perfusion

This study presents a stratified model that simulates the pulmonary capillary blood flow under influence of different lung volumes. The model includes capillary geometry, capillary wall elasticity, pressure exerted by the heart, blood viscosity, the effect of the chest wall and hydrostatic effects of the lung tissue and of the blood. The model simulates highly pulsatile blood flow with a heterogenous flow distribution down the lungs, in agreement with previous experimental studies. Moreover the model is in agreement with experimentally measured total capillary flow, total capillary volume, total capillary surface area and transition time of red blood cells passing through the pulmonary capillary network. The presented model is the first to describe the link between lung volume and perfusion.

FGF9 and SHH regulate mesenchymalVegfaexpression and development of the pulmonary capillary network

The juxtaposition of a dense capillary network to lung epithelial cells is essential for air-blood gas exchange. Defective lung vascular development can result in bronchopulmonary dysplasia and alveolar capillary dysplasia. Although vascular endothelial growth factor A (Vegfa) is required for formation of the lung capillary network, little is known regarding the factors that regulate the density and location of the distal capillary plexus and the expression pattern of Vegfa. Here, we show that fibroblast growth factor 9 (FGF9) and sonic hedgehog (SHH) signaling to lung mesenchyme, but not to endothelial cells, are each necessary and together sufficient for distal capillary development. Furthermore, both gain- and loss-of-function of FGF9 regulates Vegfa expression in lung mesenchyme, and VEGF signaling is required for FGF9-mediated blood vessel formation. FGF9, however, can only partially rescue the reduction in capillary density found in the absence of SHH signaling, and SHH is unable to rescue the vascular phenotype found in Fgf9(-/-) lungs. Thus, both signaling systems regulate distinct aspects of vascular development in distal lung mesenchyme. These data suggest a molecular mechanism through which FGF9 and SHH signaling coordinately control the growth and patterning of the lung capillary plexus, and regulate the temporal and spatial expression of Vegfa.

Childhood intrathoracic Hodgkin lymphoma with hypertrophic pulmonary osteoarthropathy: a case report and review of the literature

Hypertrophic osteoarthropathy (HOA) is characterized by clubbing, periosteal new bone formation and polyarthritis. The pathogenesis of clubbing involves an increased expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) from the digitally lodged platelet clumps, which bypass the pulmonary capillary network as a result of various systemic disorders. Intrathoracic neoplasms are rare causes of HOA in children. We report here a 14-year-old boy with digital clubbing, who eventually received the diagnosis of intrathoracic Hodgkin lymphoma (HL) and HOA. Eight cases previously reported with these two diagnoses are reviewed to emphasize the prognostic significance of HOA in childhood HL. Given the pathogenesis of clubbing and the prognostic significance of HOA, intrathoracic disease should be considered when HOA is detected in a child with a known or suspected malignant disease, and the occurrence of HOA during follow-up should alert the physicians for possible recurrence of the neoplastic disease or intrathoracic involvement.

1122 肺毛細血管網における好中球の停滞時間が濃度上昇に与える影響(J05-1 血液循環系のバイオエンジニアリング:医療技術への展開(1),J05 血液循環系のバイオエンジニアリング:医療技術への展開)

1122 肺毛細血管網における好中球の停滞時間が濃度上昇に与える影響(J05-1 血液循環系のバイオエンジニアリング:医療技術への展開(1),J05 血液循環系のバイオエンジニアリング:医療技術への展開)

Computational models of structure–function relationships in the pulmonary circulation and their validation

The pulmonary airway, arterial, venous and capillary networks are vast complex branching and converging systems that are mechanically coupled to the surrounding lung tissue. Early studies that examined vascular or airway geometry relied on measurements from casts, but medical imaging now enables measurement of the lung in vivo, at controlled lung volumes. The high-quality data that imaging provides have prompted development of increasingly sophisticated models of the geometry of the airway and pulmonary vascular trees. The accurate spatial relationships between airway, vessel and tissue in these imaging-derived models are necessary for computational analysis that aims to elucidate regional airway-vessel-tissue interactions. Predictions of blood flow through multiscale imaging-derived models of the pulmonary arteries and capillary bed reveal geometry-dependent patterns of perfusion in response to gravity and lung orientation that cannot be predicted with simplified, summary representations of the pulmonary transport trees. Validation of such predictions against measures from functional imaging holds significant potential for explaining and differentiating normal and disease-related heterogeneity in regional blood flow calculated using perfusion imaging.

Simulation model for flow of neutrophils in pulmonary capillary network

The concentration of neutrophils in the pulmonary microvasculature is higher than in systemic large vessels. It is thought that the high concentration of neutrophils facilitates their effective recruitment to sites of inflammation. Thus, in order to understand the role of neutrophils in the immune system, it is important to clarify their flow characteristics in the pulmonary microvasculature. In previous studies, we numerically investigated the motion of a neutrophil through a single capillary segment modeled by a moderate axisymmetric constriction in a straight pipe, developing a mathematical model for the prediction of the transit time of the cell through the segment. In the present study, this model was extended for application to network simulation of the motion of neutrophils. First, we numerically investigated shape recovery of a neutrophil after expulsion from a narrow capillary segment. This process was modeled in two different phases: elastic recovery and viscous recovery. The resulting model was combined with the previously developed models to simulate motion of the cells and plasma flow in a capillary network. A numerical simulation of the motion of neutrophils and plasma flow in a simple lattice capillary network showed that neutrophils were widely dispersed in the network with an increased concentration.

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.

Biologic Limits of Viability

After completing this article, readers should be able to: 1. Define the gestational range for extremely preterm birth. 2. Explain the difference between possibility and probability in reference to survival following extremely preterm birth. 3. Describe the key lung development required for adequacy of gas exchange. 4. Describe the renal functional limitations for water, sodium, and creatinine homeostasis in the first postnatal week of the extremely preterm infant. 5. List at least one structural and/or functional limitation of at least five organ systems that increases mortality risks for the extremely preterm infant. With the advent of neonatal intensive care in the 1960s, preterm infants born at progressively lower gestational ages began to survive. The progression of the decrement did not follow a recognizable relationship; rather, it was erratic as the knowledge base of neonatal physiology and pathology expanded and new technical capabilities for life support were developed. The most dramatic increase in survival of extremely preterm birth (<26 completed weeks’ gestation) came with the introduction of surfactant replacement therapy in the late 1980s. The increased use of maternal antenatal corticosteroid therapy for induction of lung maturation with threatened preterm delivery following the National Institute of Child Health and Human Development Consensus Conference recommendations in 1994 also contributed to improved survival. Since that time, the survival of infants of gestational ages as low as 22 weeks’ has been reported. The purpose of this article is to review the current understanding of the biologic factors limiting survival potential, particularly as they inform clinical decision-making. Viability or survival potential, when used in reference to a fetus, frequently is used to indicate the possibility for a fetus to be live born and capable of living to a specified endpoint of either a designated time, reaching a certain age or a landmark event, admission to a neonatal intensive care unit, …

Transit Characteristics of a Neutrophil Passing through Two Moderate Constrictions in a Cylindrical Capillary Vessel (Effect of Cell Deformation on Transit through the Second Constriction)

Neutrophils must flow through the pulmonary capillary network in a deformed shape because pulmonary capillaries are closely interconnected, and deformed neutrophils take about 15 s to 1 min to return to their resting spherical shape. In this paper, flow of a neutrophil through two moderate constrictions in a pipeline is numerically investigated, focusing on the effect of cell deformation on the cell's transit time through the constrictions. Changing sizes and positions of the constrictions, we found that the maximum cell radius at the entrance of the constriction and the throat radius of the constriction are the dominant factors in predicting the cell's transit time through the constriction. When the difference between these two radii is relatively large, steeper constriction (smaller radius of curvature) increases the transit time, but this tendency is reversed when the difference is small. Cells traverse the constriction without delay when the maximum cell radius and throat radius are comparable. Finally, we present a simple mathematical model for the transit time.

Transit Characteristics of a Neutrophil Passing Through a Circular Constriction in a Cylindrical Capillary Vessel. Effect of Mechanical Properties of the Cell and Constriction Geometry.

The former analysis of neutrophil's transit through pulmonary capillary network used the result of a micropipette aspiration experiment to model the transit in single capillary segment despite blunt tip geometry of the pipette is largely different from the real capillary segment. In the previous work, we have numerically investigated the transit of passive and fMLP-stimulated neutrophils through an arc-shaped constriction, establishing the analytical expression for the transit time. This paper intends to give a simplified model for the transit of a neutrophil through a capillary segment based on the numerical analysis and the stress strain relationship of a Maxwell material. It is shown that the transit time is in proportion to the viscosity of the cell and in inverse proportion to the square root of the curvature radius of the constriction. The definition of the driving pressure of the cell into a micropipette is also applicable to that into the constriction.

Tubes, Branches, and Pillars

The angiogenic cascade is getting increasingly complex. A few years ago, vasculogenesis and angiogenesis were considered as the primary mechanisms leading to the formation of new blood vessels. The original definition of vasculogenesis denotes the formation of a primary embryonic vascular network from in situ differentiating angioblastic cells.1 In contrast, angiogenesis primarily referred to the sprouting of blood vessels from preexisting vessels.1 Recent advances in the identification of molecules that regulate angiogenesis and vascular remodeling have shown that the simplistic model of an invading capillary sprout is not sufficient to appreciate the whole spectrum of morphogenic events that are required to form a neovascular network (Figure 1).1–3 Undoubtedly, vascular endothelial growth factor (VEGF) acts at an early point in the hierarchical order of morphogenic events and probably fulfills all criteria to be considered as a master switch of the angiogenic cascade. In contrast, the angiopoietins and their receptor Tie-2 as well as the ephrins and their corresponding Eph receptors appear to act at a somewhat later stage of neovessel formation. These molecules orchestrate a number of related, yet functionally and molecularly not well understood, processes such as vessel assembly (network formation and formation of anastomoses), vessel maturation (recruitment of mural cells [pericytes and smooth muscle cells], and extracellular matrix assembly, pruning of the primary vascular bed), and acquisition of vessel identity (formation of arteries, capillaries, and veins)3,4 (Figure 2). Lastly, the mechanisms of organotypic differentiation of the vascular tree (continuous endothelium, discontinuous endothelium, fenestrated endothelium) are not at all understood and the first molecules that govern subpopulation-specific vascular growth and differentiation are just being uncovered.5,6 Figure 1. Change of paradigm. From sprouting angiogenesis to vascular morphogenesis. Basement membrane degradation, directed endothelial cell migration, and proliferation (left) were considered as the primary mechanisms of angiogenesis. …

Computer determination of perfusion patterns in pulmonary capillary networks.

Individual pulmonary capillaries are not steadily perfused. By using in vivo microscopy, it can readily be demonstrated that perfusion continually switches between capillary segments and between portions of the network within a single alveolar wall. These changes in capillary perfusion occur even when upstream pressure and flow are constant. Flow switching between capillary segments in the absence of hemodynamic changes in large upstream vessels suggests that capillary perfusion patterns could be random. To calculate the probability that perfusion patterns could occur by chance, it is necessary to know the total number of possible perfusion patterns in a given capillary network. We developed a computer program that can determine every possible perfusion pattern for any given capillary network, and from that information we can calculate whether perfusion of individual segments in the network is random. With the results of the computer program, we have obtained statistical evidence that some capillary segments in a network are nonrandomly perfused.

PULMONARY MICROCIRCULATION DURING PULSATILE AND NONPULSATILE PERFUSIONS

During development of a rotary blood pump as an assist device, the efficacy of non pulsatile perfusion to the end organ has to be verified. However, there are few evaluations of two different perfusion mechanisms through the tissue microcirculation. In this study, the pulmonary microcirculation was analyzed by vital microscopic observation. Wistar rats weighing 400-500 g were anesthetized and ventilated by a respirator. After establishing right heart bypass from the right atrium to the pulmonary artery using a roller pump, the pulmonary microcirculation was observed during intravenous infusion of bovine albumin tagged with fluorescein isothiocyanate. The images were recorded on a videotape through an ultra-sensitive SIT TV camera. Initially, the pulmonary circulation was pulsatile, produced by the native heart, and the pulmonary capillary network was evenly perfused by the blood. After starting the pump, the flow became non pulsatile and the distribution of capillary perfusion was displaced to the short circuit connecting the pulmonary arterioles and venules. Flow distribution during non pulsatile perfusion was heterogeneous compared with pulsatile perfusion. This result suggests that non pulsatile flow may lead to the deterioration of function. Further investigation is necessary to evaluate the relationship between the microcirculation and organ function.

Lipolysaccharide-induced monocyte retention in the lung. Role of monocyte stiffness, actin assembly, and CD18-dependent adherence.

Abstract Blood monocytes and monocyte-derived macrophages accumulate in the lungs and can modulate pulmonary inflammatory and reparative processes through their elaboration of cytokines and growth factors. Endotoxemia, often a prelude to acute lung injury, induces a monocytopenia, likely resulting from monocyte accumulation in the lung. We hypothesized that LPS would induce monocyte lung retention by increasing monocyte stiffness and thereby diminishing the cell's ability to deform and transit the narrow pulmonary capillary network, and that LPS would induce CD18-dependent adhesion of monocytes to endothelium, prolonging their retention. LPS induced a rapid and concentration-dependent increase in human monocyte stiffness, net filamentous actin assembly, and retention in a filtration model of pulmonary capillaries. These LPS-induced responses were dependent on the integrity of actin filaments in that cytochalasin D, an agent that disrupts filamentous actin assembly, attenuated each of these processes. LPS induced CD18-dependent and -independent human monocyte adhesion to unstimulated human endothelial cell monolayers. In vivo, rabbit monocytes were retained in the lungs of animals rendered endotoxemic. Pretreatment of monocytes ex vivo with LPS enhanced their lung retention suggesting that LPS was acting directly on monocytes. Initial lung retention during endotoxemia was attenuated by inhibiting monocyte F-actin assembly with cytochalasin D. Anti-CD18 Abs caused a slight decrease in initial retention of monocytes, but led to a 90% inhibition of retention by 2 h. Control IgG had no effect. These data suggest that the initial retention of monocytes in the lung during endotoxemia is dependent on alterations in their stiffness and assembly/organization of F-actin, and that CD18-dependent adhesive mechanisms prolong monocyte retention in the lung during this process.

Effect of increasing flow on distribution of pulmonary capillary transit times

The complex morphology of the pulmonary capillary network causes capillary transit times to be dispersed about a mean. It is known that flow-induced decreases in mean capillary transit time are partially offset by capillary recruitment and distension, but the effect of these factors on the rest of the distribution of transit times is unknown. We have studied the relationship between blood flow, capillary recruitment, and the distribution of transit times in isolated canine lungs with videomicroscopy. Doubling baseline lobar blood flow recruited capillaries. All transit times in the distribution decreased, as did relative dispersion. Doubling flow again caused a further decrease in transit times, but neither capillary recruitment nor relative dispersion changed significantly. We conclude that capillary transit times become more homogeneous as lobar flow increases from low to intermediate levels. Further increases in flow across a fully recruited network are associated with decreases in transit times but not with more homogeneous capillary perfusion.

Demonstration of pulmonary vascular perfusion by electron and light microscopy

To estimate the fraction of dense pulmonary capillary network that is perfused under physiological conditions, we developed a new method for the demonstration of in vivo capillary perfusion by light and electron microscopy. Blood plasma was labeled by 8-nm colloidal gold particles coated with rabbit serum albumin. In anesthetized rabbits, 4-5 ml of this tracer were injected into the right atrium. Two and 15 min later, the circulation was interrupted by a snare around the heart, and the lung was fixed by instillation with glutaraldehyde. Gold particles were found in the plasma space of alveolar capillaries as well as in other organs. A random sample of thin sections studied by electron microscopy revealed that the entire capillary bed of the lung was perfused at least with plasma within 2 min after tracer infusion. Light microscopy of silver-enhanced sections showed areas with different staining intensities but no obviously unperfused capillaries. The concept of capillary recruitment, which would require a significant fraction of capillaries unperfused at rest, may have to be reassessed to consider time factors as well as the two-phase nature of blood; red blood cells and plasma may take different paths.

Distribution of pulmonary capillary transit times in recruited networks

When pulmonary blood flow is elevated, hypoxemia can occur in the fastest-moving erythrocytes if their transit times through the capillaries fall below the minimum time for complete oxygenation. This desaturation is more likely to occur if the distribution of capillary transit times about the mean is large. Increasing cardiac output is known to decrease mean pulmonary capillary transit time, but the effect on the distribution of transit times has not been reported. We measured the mean and variance of transit times in single pulmonary capillary networks in the dependent lung of anesthetized dogs by in vivo videofluorescence microscopy of a fluorescein dye bolus passing from an arteriole to a venule. When cardiac output increased from 2.9 to 9.9 l/min, mean capillary transit time decreased from 2.0 to 0.8 s. Because transit time variance decreased proportionately (relative dispersion remained constant), increasing cardiac output did not alter the heterogeneity of local capillary transit times in the lower lung where the capillary bed was nearly fully recruited.

Influence of maternal diabetes on basement membranes, type 2 cells, and capillaries in the developing rat lung

To determine the effect of maternal diabetes on rat lung development, we studied the ultrastructure of the alveolar wall from the ninteenth day of gestation (term = 22 days) through the eighth postnatal day in fetal and neonatal rats of mothers with streptozotocin-induced diabetes. In normal fetal lung development, epithelial basement membranes develop large discontinuities beneath type 2 cells, through which cytoplasmic foot processes extend into the interstitium. Maternal diabetes delays the appearances of these epithelial basement membrane discontinuities and reduces the number of type 2 cell processes that penetrate it. These alterations in epithelial basement membrane are reversed after birth. There is no ultrastructural evidence of a delay in type 2 cell maturation as assessed by lamellar body volume density morphometry. Endothelial basement membranes, which are not present around the growing pulmonary capillary bed in the pseudoglandular lung, are seen late in normal gestation, primarily around capillaries forming the mature air-blood barrier. This development of endothelial basement membrane may be delayed in the fetuses of diabetic mothers and reflects a significant delay in the expansion of the pulmonary capillary network in these animals as assessed by morphometric volume density measurements. This effect on capillary growth is not reversed in the newborn animals through 8 days after birth. The summation of these effects indicates a generalized slowing of fetal lung development by maternal diabetes, some of which effects persist after birth and may continue to influence lung development during the period of postnatal alveolar septal growth.