Vasculogenesis drives pulmonary vascular growth in the developing chick embryo.

Formation of the pulmonary vasculature has been described as occurring by outgrowth of existing vessels (angiogenesis), de novo formation of new vessels (vasculogenesis), or a combination of both processes. Uncertainty about the contribution of angiogenesis and vasculogenesis to pulmonary vascular formation is partly due to methodologic approaches. Evidence in favor of angiogenesis stems from studies that used vascular-filling methods. Such methods identify only directly continuous lumina. Evidence for vasculogenesis has been provided by the use of molecular markers of blood vessel endothelium. Use of both methods has not been combined in the same species, however. We hypothesized, based on published evidence from quail and mouse, that chick pulmonary vascular formation occurs by vasculogenesis. To test that hypothesis, we used vascular filling, serial section, and immunohistochemical methods to analyze the developing lungs of chick embryos from Hamburger and Hamilton stages 20 to 43. Vascular filling suggested that the lumen of the pulmonary arteries sprouted from the sixth pharyngeal arch arteries. However, serial sections and immunohistochemical localization of fetal liver kinase-1 protein, the receptor for vascular endothelial growth factor, showed that the pulmonary arterial tree formed from endothelial cell precursors and coalescence of isolated blood vessels in the mediastinal splanchnic mesenchyme centrally to the developing lung tissue distally. Pulmonary veins grew from the left atrium to the developing lungs. Pulmonary blood vessel formation occurred continuously throughout the embryonic period studied. Our results show that vasculogenesis is the main process by which the pulmonary vasculature forms in the developing chick embryo.     

Qualitative and quantitative analysis of embryonic pulmonary vessel formation

Vessel formation in the lung has been described as occurring by two mechanisms: proximal, or branch, pulmonary arteries develop via angiogenesis; and distal, smaller vessels form by vasculogenesis. Connections between the proximal and distal vessels establish the final vascular network. The preponderance of vessel formation has been suspected to occur during the canalicular stage of lung development. To test these hypotheses, reporter gene expression under control of the regulatory domain of fetal liver kinase-1 (flk), an early endothelial cell-specific marker, was used to evaluate mouse lungs from embryonic day 10.5 (E10.5) through 2 wk postnatal age. Morphologic assessment was performed after histochemical staining, and quantification of vessel development by a chemiluminescent assay was compared with overall embryonic lung growth. LacZ expression under flk promoter control allowed: (1) early identification of differentiating endothelial cells of the branch pulmonary arteries; (2) visualization of distal vessels forming in the lung mesenchyme (primary capillary network) with subsequent remodeling; (3) recognition of early continuity between proximal and distal vessels, occurring by E10.5; and (4) assessment of developing pulmonary veins and venous confluence. Quantitative analysis revealed increased flk regulated beta-galactosidase (beta-gal) activity of 12 ng beta-gal/lung at E12.5 to 3,215 ng beta-gal/lung at 2 wk, which corresponded to overall lung growth during this period as shown by an increase in total protein content per lung from 35 microg at E12.5 to 6,456 microg at 2 wk after birth. We identified endothelial cell precursors of the developing pulmonary vasculature before vessel lumen formation. Continuity between the proximal pulmonary artery and vessels forming in the distal mesenchyme was present even at the earliest stage evaluated, suggesting endothelial cell differentiation at the site of vessel formation (i.e., vasculogenesis) as occurs with development of the aorta. Finally, we demonstrated that lung vessel development was not accentuated during the canalicular stage, but occurred at all stages and directly corresponded to overall lung growth.     

Accuracy and variability assessment of a semiautomatic technique for segmentation of the carotid arteries from three-dimensional ultrasound images

In this paper, we report on a semiautomatic method for segmentation of three-dimensional (3D) carotid vascular ultrasound (US) images. Our method is based on a dynamic balloon model represented by a triangulated mesh. The mesh is manually placed within the interior of the carotid vessels, then is driven outward until it reaches the vessel wall by applying an inflation force to the mesh. Once the mesh is in close proximity to the vessel wall, it is further deformed using an image-based force, in order to better localize the boundary. Since the method requires manual initialization, there is inherent variability in the position and shape of the final segmented boundary. Using a 3D US image of a patient's carotids, we have examined the local variability in boundary position as the initialization position is varied throughout the interior of the carotid vessels in the 3D image. We have compared the semiautomatic segmentation method to a fully manual segmentation method, and found that the semiautomatic approach is less variable than the intraobserver variability for manual segmentation. We have furthermore examined the accuracy of the semiautomatic method by comparing the average surface to an "ideal" surface, determined by the average manually segmented surface. We have found, in general, good agreement between the semiautomatic and manual segmentation methods. For the 3D US image in question, the mean separation between the average segmented surface and the gold standard was found to be 0.35 mm. The two surfaces were determined to agree with each other, within uncertainty, at 65% of the mesh points comprising the two surfaces.     

肺栓塞肺动脉能谱CT胸部扫描影像学特征及其诊断价值

目的：探讨肺栓塞（PE）肺动脉能谱CT胸部扫描影像学特征及其诊断价值。方法：回顾性分析53例高度疑似PE患者,获取单能量能谱CT肺动脉造影（CTPA）图像和碘基肺灌注图,记录CTPA图像和碘基肺灌注图检出的肺动脉栓子数目及其分布、分型情况;分析肺动脉能谱CT胸部扫描影像学特征;比较不同栓塞程度及类型能谱CT扫描碘基值;比较栓塞区与对照区能谱CT扫描碘基值、水基值和CT值等能谱CT扫描参数。结果：以CTPA为金标准,53例高度疑似PE的患者中确诊32例。能谱CTPA检出162个栓子,完全型栓子37个,非完全型栓子125个;碘基肺灌注图检出171个栓子,完全型栓子49个,非完全型栓子122个。中心型、偏心型和完全型栓子栓塞区能谱CT扫描碘基值均明显低于对照区（P<0.05）;附壁型栓子栓塞区能谱CT扫描碘基值与对照组无显著差异（P>0.05）;完全型栓塞区碘基值显著低于中心型、偏心型和附壁型等非完全型栓塞区（P<0.05）。结论：PE肺动脉能谱CT胸部扫描影像学特征主要表现为肺动脉内充盈缺损、肺动脉扩张、肺动脉高压、马赛克征、轨道征等征象,肺动脉能谱CT胸部扫描碘基肺灌注...     

Fluid mechanics of the pulmonary circulation

Assessment of the fluid mechanics of the pulmonary circulation has been hindered by the relative inaccessibility of the pulmonary vascular bed. Current understanding is based largely on analyses of mathematical models which have been used to simulate hemodynamic characteristics within an architectural representation of that bed. These representations have ranged from simple, lumped parameter structures to anatomically realistic structures based on measurements of casts of the irregular branching network of pulmonary arteries and veins. Nonlinear models have been studied to determine the effects of vessel taper and within beat geometrical variations as cross-sectional shapes change from circular to elliptical and small vessels undergo recruitment, distention, and collapse as a result of the shifting balance in alveolar, pleural, and capillary pressures. This article reviews current concepts of pulmonary circulatory fluid mechanics focusing on mathematical models and relevant hemodynamic studies.     

Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: Histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics

In patients presenting with idiopathic pulmonary fibrosis (IPF), modifications of pulmonary vessels are well defined in fibrotic areas but have not been accurately assessed in the intervening patches of preserved lung. Moreover, the relation between pulmonary vessel lesions and pulmonary hemodynamics is not well known. We therefore designed a retrospective study on lung explant specimens from 26 patients with a firm diagnosis of IPF who had undergone lung transplantation. Our aim was to (1) describe the vascular lesions, especially in preserved lung areas, and (2) correlate them with pulmonary hemodynamics. In dense fibrotic zones, thickening of the arterial and venous wall with severe luminal narrowing was present in each patient. In architecturally preserved lung zones, occlusion of venules and small pulmonary veins was observed in 65% of the patients, although there were only mild changes of muscular pulmonary arteries. We found a significant positive correlation between the macroscopic extent of lung fibrosis and mean pulmonary artery pressure, but we failed to find a relation between mean pulmonary artery pressure and venous/venular lesions in nonfibrotic areas. Our study points out that in many patients with IPF, nonfibrotic lung areas demonstrate an occlusive venopathy, the signification of which remains undetermined.     

Airway and blood vessel interaction during lung development

In the adult lung the pulmonary arteries run alongside the airways and the pulmonary veins show a similar branching pattern to the arteries, though separated from them. During early fetal development the airways act as a template for pulmonary blood vessel development in that the vessels form by vasculogenesis around the branching airways. In later lung development the capillary bed is essential for alveolar formation. This paper reviews evidence for the interaction of the airways and blood vessels in both normal and abnormal lung development.     

Quantitative evaluation of vessel tracking techniques on coronary angiograms.

Accurate, automated determination of vessel center lines is essential for two- and three-dimensional analysis of the coronary vascular tree. Therefore, we have been developing techniques for vessel tracking and for evaluating their accuracy and precision in clinical images. After points in vessels are manually indicated, the vessels are tracked automatically by means of a modified sector-search approach. The perimeters of sectors centered on previous tracking points are searched for the pixels with the maximum contrast. The sector size and radius are automatically adjusted based on local vessel tortuosity. The performance of the tracking technique in regions of high-intensity background is improved by application of a nonlinear adaptive filtering technique in which the vessel signal is effectively removed prior to background estimation. The tracking results were evaluated visually and by calculation of distances between the tracked and user-indicated centerlines, which were used as the "truth." Two hundred and fifty-six coronary vessels were tracked in 32 angiograms. Vessels as small as 0.6 mm in diameter were tracked accurately. This technique correctly tracked 255/256 (>99%) vessels based on an average of 2-3 indicated points per vessel. The one incorrect tracking result was due to a low signal-to-noise ratio (SNR<2). The distance between the tracked and the "true" centerlines ranged from 0.4 to 1.8 pixels, with an average of 0.8 pixels. These results indicate that this technique can provide a reliable basis for 2D and 3D vascular analysis.     

4种肺动脉高压动物模型肺血管重构模式的差异研究

目的：探讨4种肺动脉高压（PH）动物模型肺血管重构模式的差异。方法:雄性SD大鼠（350-400g），分别通过腹主动脉-腔静脉分流（A-VF, n=10）、左肺切除（PE, n=10）、野百合碱注射（MCT, n=10）、左肺切除+MCT（PE+MCT,n=12）4种方法建立PH模型。检测平均肺动脉压力(mPAP）、RV/(LV+S)重量比值、肺小动脉中膜厚度百分比（WT%）、无肌性动脉肌化程度和新生内膜(neointima)形成、新生内膜增殖度和血管阻塞计分（VOS）。结果:在PE+MCT组（肺切除术后5周，MCT注射后4周）右肺腺泡内血管出现了新生内膜病变，其它组均没有新生内膜病变形成。PE+MCT组的动物出现了严重的右心室肥大，动脉中膜明显增厚，平均肺动脉压（mPAP）和无肌性血管肌化程度显著增加；A-VF、PE和MCT组仅形成轻-中度的右心室肥大、mPAP升高和小动脉肌化。结论:左肺切除联合应用MCT能成功诱导大鼠PH新生内膜模型，该模型能更好地模拟人类严重PH的病理改变，是研究梗阻性PH更为适用的动物模型。     

Injury and remodeling of pulmonary veins by high oxygen. A morphometric study.

Breathing 87% oxygen at normobaric pressure for 28 days injuries and remodels the wall of distal pulmonary veins (less than or equal to 150 mu). Occluded vessels are evident, as are vessel remnants in which wall integrity is lost (obliterated vessels). Significantly more veins have a muscular or partially muscular wall than normal (P less than or equal to 0.001 for veins in each size category less than or equal to 150 mu, chi-square test). In some veins new muscle develops between an external and internal lamina but in many it develops within the intima, beneath the endothelium and adluminal to a single lamina. Small veins (20-25 mu in ED) with a muscular or partially muscular wall are present only in the hyperoxic lung. Increase in the percent medial thickness (%MT) of veins indicates lumen narrowing: this is relatively greater in the smallest veins. Reduction in the cross-sectional area of venous segments that are immediately postcapillary, by lumen narrowing or occlusion, contributes to the restriction of the pulmonary vascular bed by hyperoxia.     

Pulmonary lymphatic filling is increased in spontaneously hypertensive rats

Extravascular lung liquid must rely on tissue-space pressure gradients to drive it into the lymphatics because the fluid is outside the lymphatic contractile pumping and valve control. Focal tissue pressure changes could result from muscular contraction in the blood vessel walls. Perivascular lymphatics usually lie within the adventitia of pulmonary blood vessels, and are generally more noticeable in veins than arteries. Spontaneously hypertensive rats have exaggerated focal pulmonary venous muscle (venous sphincters). These muscular tufts are often near initial lymphatics; if their contraction was important for lymph transport, spontaneously hypertensive rats could have more lymphatic filling in the areas of the pulmonary venous sphincters than normotensive rats. Because the focal muscularity is found in pulmonary veins more than arteries, veins may have more focal lymphatic filling than arteries. To test these hypotheses, lung histology and vascular and lymphatic casts of spontaneously hypertensive and normotensive rats were examined. Contracted venous sphincters were found on 108 of 127 veins with lymphatics in the spontaneously hypertensive rats and 5 of 41 in the normotensive rats P<0.01). The spontaneously hypertensive rats had deeper venous contractions and more lymphatic filling around both arteries and veins (P<0.01). In the hypertensive rats, the venous was greater than the arterial lymphatic filling (P<0.01). On the pleural surface, hypertensive rats also had greater lymphatic filling than controls (P<0.01). This anatomic evidence suggests that pulmonary venous sphincters are associated with focal lymphatic filling, and perivascular muscle action might be a component of the pulmonary lymphatic system.     

肺密度三维定量分析对急性肺栓塞的诊断价值

【摘要】目的:探讨肺密度三维定量分析对急性肺栓塞的诊断价值。方法:回顾性收集行CT肺动脉造影（CTPA）检查者,证实为肺栓塞者195例,非肺栓塞者177例,两位影像科医生对CTPA进行阅读,记录栓子位置以及间接征象。结果:肺栓塞患者最常见的临床症状气促、咳嗽、胸痛分别占41%、39%、34%。53%的肺栓塞患者具有明确的危险因素。共发现412个栓子,间接征象在急性肺栓塞和非肺栓塞患者中出现率具有显著性差异（P<0.05）,包括:马赛克征（20.3％ vs 0％）、磨玻璃影（23.1% vs 9.4%）、肺实变（46.7% vs 18.8%）、肺不张（17.2% vs 2.8%）、胸腔积液（34.9% vs 23.3%）、胸膜肥厚粘连（77.8% vs 25.1%）。肺密度分析发现的肺野局限性低密度区在栓塞组和非栓塞组具有差别（47.2% vs 13.9%, P<0.05）。且局限性密度减低区与栓子位置的符合率为89.2%。结论:基于肺密度三维定量分析获得的局限性肺密度改变,结合肺栓塞患者的临床信息与CTPA其他间接征象对急性非栓塞诊断具有提示作用。     

Variations of pulmonary vessels: Some practical implications for lung resections

Anatomical variations of the bronchi and lung vessels may be important obstacles during lung resection if overlooked. We designed this study to determine the frequency and types of variations of lung vessels during lung resections. In a 3[1/2]‐year‐period, anatomical variations were recorded and registered by digital photography at the hilar and/or interlobar areas during lung resection surgery on 140 patients. Variations of the pulmonary blood vessels were observed in 23 patients. Of these, 12 patients had variations of the middle lobe vessels. Middle lobe veins emptying into the right inferior pulmonary vein, and middle lobe arteries originating from the artery for the basal segments, were observed in four patients each; two separate middle lobe arteries and a low origin of the middle lobe artery existed in three and one patient, respectively. Among seven patients with variations of the lingular vessels, the lingular artery originating from the artery for the basal segments was found in three patients; the remaining variations referred to absent or low origin of the lingular artery (in one patient each), and to an aberrant lingular vein, separate from the upper lobe vein (two patients). A single unilateral pulmonary vein and a left‐sided bronchial tree completely behind the pulmonary artery existed in three and one patient, respectively. Potential problems related to these variations during resectional lung surgery are discussed. Awareness of the most frequent variations is of utmost importance for safe lung resections. Clin. Anat. 22:698–705, 2009. © 2009 Wiley‐Liss, Inc.     

Transformation of the fungus ball type pulmonary aspergillosis]

Though the concept of semi-invasive pulmonary aspergillosis was advocated in 1981 by Gefter et al., its histopathological appearance has not yet been reported in detail. Pathological studies on fungus ball type pulmonary aspergillosis (PA) were originally made mainly in regard to related bronchi. Chronic-progressive destructive changes cannot be completely explained from this viewpoint alone. Clinically, since bloody sputum and hemoptysis appeared frequently, further studies on the pulmonary vasculature were considered necessary. In the resected lungs of 3 cases of semi-invasive pulmonary aspergillosis, the pathological features of pulmonary vasculature were characterized by numerous fungal clots within pulmonary arteries and veins, marked destruction of pulmonary blood vessels and extensive intravascular fibrin deposition. Intravascular fibrin deposition causes stasis of blood flow, promotes intravascular proliferation of aspergilli and probably accelerates pulmonary destruction caused by blood stasis. Important pathological findings of fungus ball type pulmonary aspergillosis of the semi-invasive subtype with clinical aspects of chronic-progressive lung destruction caused by severe inflammation, were reported for both the vascular and the bronchial system.     

Repeated pulmonary thromboembolism in rabbits.

Ten rabbits received 24 to 76 intravenous injections of finely divided thrombi prepared by a modification of Chandler's apparatus. Eight rabbits were killed soon after the last injection (group A) and two rabbits were allowed to survive for 4 months after the last introduction of thrombi (group B). Ten rabbits received repeated saline injections only, and six animals underwent no manipulation whatever. Six test rabbits and six control rabbits underwent catheterization of the pulmonary artery. The pulmonary arteries of each lung received injections of radiopaque material and were x-rayed; multiple blocks were selected from each lobe of each lung, cut, and stained with Weigert's elastic Van Gieson's stain, which permitted measurement of arterial medial thickness. Sections were also stained with hematoxylin and eosin and Martius scarlet blue. The results of catheterization showed that only mild pulmonary hypertension had been induced. Histologically, thromboemboli had become incorporated into the wall of the arteries. Concentric intimal thickening included an "onionskin" arrangement and was more prevalent than eccentric configuration. Medial hypertrophy of almost all vessels was found. The onionskin arrangement in an occasional precapillary vessel was also encountered. More severe histologic grades of pulmonary hypertension were not seen. The two group B animals showed recent thrombi, which suggested that once intimal thickening had occurred the process of fresh thrombotic superimposition continues, resulting in progression of the lesions. The experimental findings were compared with 13 patients (thromboembolic pulmonary hypertension (eight) and primary pulmonary hypertension (five)) and with 181 patients reported in the literature. Features such as the onionskin type of intimal thickening in muscular arteries and precapillary vessels have been suggested as points of distinction between these two conditions. These features have been reproduced in these experiments. Despite the fact that more severe histologic grades of pulmonary hypertension were not produced, it is suggested that these experiments lend support to the concept that primary pulmonary hypertension may have a thromboembolic etiology in at least some patients.     

Influence of hypobaric hypoxia in infancy on the subsequent development of vasoconstrictive pulmonary vascular disease in the Wistar albino rat

A group of Wistar albino rats was injected subcutaneously with monocrotaline to induce vasoconstrictive hypertensive pulmonary vascular disease characterized by medial hypertrophy of small pulmonary arteries, the appearance of muscular pulmonary arterial vessels of arteriolar dimensions (less than 20 microns) in diameter), and exudative changes in the lung parenchyma. The vascular abnormalities were quantified by measuring the percentage medial thickness of small pulmonary arteries, the number of muscular pulmonary arterial vessels below 20 microns in diameter per cm2 of lung section and by determining the smallest arterial vessels in each case showing muscularity. A second group of rats was born in a decompression chamber and kept in hypobaric hypoxia for a month of the neonatal period, developing hypoxic hypertensive pulmonary vascular disease as a consequence. The animals in this group were allowed to recover in room air for a period of 3 months and were then injected with the same dose of monocrotaline as that given to the first group. The rats previously exposed to hypoxia exhibited an exaggerated response to the alkaloid, showing in particular many more small muscular pulmonary arterial vessels which were of a smaller diameter than those found in the eupoxic rats treated with the alkaloid. The experiment demonstrates the perinatal hypoxia exaggerates the effects of agents inducing vasoconstrictive pulmonary hypertension with a shift of the segment of the pulmonary arterial tree involved to the periphery as in hypoxia. Reports of a similar phenomenon are noted as occurring in babies born at high altitude, spending their infancy there and subsequently developing primary pulmonary hypertension later in life.     

Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension

The cases of two female infants with persistent neonatal pulmonary hypertension are described. Combinations of pulmonary parenchymal lesions were present, including underdevelopment of alveoli and interstitial fibrosis as well as misalignment of lung vessels. As a result of the misalignment, the pulmonary veins joined the pulmonary arteries, rather than following a course away from them. One of the infants had additional congenital malformations. This syndrome should be considered in the evaluation of infants with persistent fetal circulation.     

Three-Dimensional Reconstruction of Pulmonary Arteries in Plexiform Pulmonary Hypertension Using Cell-Specific Markers : Evidence for a Dynamic and Heterogeneous Process of Pulmonary Endothelial Cell Growth

The plexiform lesions of severe pulmonary hypertension (PH) are complex vascular structures composed primarily of endothelial cells. In this study, we use immunohistochemical markers to identify the various cell layers of pulmonary vessels and to identify different endothelial cell phenotypes in pulmonary arteries affected by severe PH. Our computerized three-dimensional reconstructions of nine vessels in five patients with severe PH demonstrate that plexiform (n = 14) and concentric-obliterative (n = 6) lesions occur distal to branch points of small pulmonary arteries. And, whereas plexiform lesions occur as solitary lesions, concentric-obliterative lesions appear to be only associated with, and proximal to, plexiform structures. The endothelial cells of plexiform lesions express intensely and uniformly the vascular endothelial growth factor (VEGF) receptor KDR and segregate phenotypically into cyclin-kinase inhibitor p27/kip1-negative cells in the central core of the plexiform lesion and p27/kip1-positive cells in peripheral areas adjacent to incipient blood vessel formation. Using immunohistochemistry and three-dimensional reconstruction techniques, we show that plexiform lesions are dynamic vascular structures characterized by at least two endothelial cell phenotypes. Plexiform arteriopathy is not merely an end stage or postthrombotic change--it may represent one stage in an ongoing, angiogenic endothelial cell growth process.     

Myointimal plaques in pulmonary vascular sclerosis associated with interstitial lung fibrosis.

In interstitial fibrosis of the lung, pulmonary vessels show priminent sclerotic changes. We have studied arteries in lung biopsies from patients with lung fibrosis of varied etiology using light and electron microscopy. It was found that the sclerotic change is essentially confined to arteries within fibrotic areas, areas of "nonfibrotic" lung having vessels with no intimal thickening. The changes are most striking in arteries with an external diameter of 500 micrometer. or greater (p less than 0.001), although smaller sized vessels also show significant changes. Ultrastructurally, the plaques are composed of typical smooth muscle cells with basement lamina, pinocytotic vesicles, dense bodies, and cytoplasmic microfilaments. These arterial changes could result from damage to the blood vessel which accompanies the mechanism producing lung fibrosis. Alternatively, the myointimal change could conceivably be part of an adaptive response following the establishment of fibrosis. In either instance, the narrowing would decrease blood flow to physiologically disadvantaged areas of the lung, and the muscle fibers might play an active role in reducing the blood flow.