肺高血流模型大鼠肺动脉重构与奈必洛尔的影响

背景：血管舒张型肾上腺素β1受体阻断药奈必洛尔能否有效降低肺动脉压,对肺血管重构有何影响,目前尚不清楚。 目的：观察奈比洛尔对肺高血流模型大鼠肺动脉重构的影响。 方法：将40只SD大鼠随机均分为4组,模型组、奈比洛尔组、卡托普利组均制备肺动脉高压并肺血管重构大鼠模型,假手术组仅分离腹主动脉及下腔动脉;造模后5 d,奈比洛尔组、卡托普利组分别于灌胃给予奈比洛尔溶液1 mg/(kg•d)与卡托普利溶液5 mg/(kg•d),模型组与假手术组灌胃给予等体积生理盐水。给药8周后,对比4组平均肺动脉压、右心室肥厚指数、肺动脉形态学变化、肺动脉超微结构及肺动脉环舒张率。 结果与结论：与假手术组比较,模型组大鼠肺间小动脉肌化  程度明显,平均肺动脉压和右心室湿质量/(左心室湿质量+室间隔湿质量)显著增高(P < 0.01或P < 0.05),肺动脉环舒张率降低(P < 0.05或P < 0.01)。与模型组比较,奈必洛尔组、卡托普利组平均肺动脉压、右心室湿质量/(左心室湿质量+室间隔湿质量)显著降低   (P < 0.05或P < 0.01),肺间小动脉肌化程度降低,肺动脉环舒张率增加(P < 0.05或P < 0.01)。说明奈比洛尔能够减轻肺高血流模型大鼠的肺动脉重构,其机制与奈必洛尔保护血管内皮和降低肺动脉压有关。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程      

Capillary remodeling in bleomycin-induced pulmonary fibrosis.

Lung fibrosis is a process in which collagen is laid down and the delicate capillary-alveolar relationship is disturbed. The architectural changes which occur in the capillaries, a main element of the oxygen transferring unit, are difficult to illustrate without a three-dimensional tool, such as scanning electron microscopy. Therefore, a scanning electron microscopic study was undertaken to show the capillary changes of lung fibrosis. Fibrosis was induced in rats by intratracheal instillation of bleomycin. After 30 days the rats were sacrificed, and the vascular tree of the lung was cast with methacrylate. The fibrosis was patchy. The intercapillary space became wider; and some capillaries had large, irregular dilatations. Occasionally giant capillaries (up to 19 mu in diameter) were noted. The pleural and alveolar capillary diameters increased (P less than 0.01), and the branching frequency decreased (P = 0.02). The center of the capillary rings, which has been suggested to be the site of contractile interstitial cells, increased in size (P = 0.03). The appearance of irregularly shaped capillaries and an increase in diameter without a change in density of alveolar capillaries, resulting in a loss of surface area and a decrease in branching, are the main scanning electron microscopic findings of the remodeling which occurs in pulmonary capillaries in lung fibrosis. These changes may partially explain the functional derangement of this disease.     

Tissue remodeling of rat pulmonary artery in hypoxic breathing. II. Course of change of mechanical properties

When cells and the matrix of a tissue remodel, the mechanical properties of the tissue do change. The mechanical properties are expressed by constitutive equations. In this article the remodeling of the constitutive equation of the pulmonary artery is studied. The remodeling was induced in a rat breathing a gas whose oxygen concentration was suddenly decreased as a step function of time and maintained constant (17.2%, 13.6%, or 10%) afterwards. Since the mathematical form of the constitutive equation has been identified in earlier papers, we need to determine only the elastic constants that change in the process of tissue remodeling. We consider arteries subjected to blood pressure and longitudinal stretch, and limit ourselves to two-dimensional problems involving only circumferential and longitudinal stress and strain. In the neighborhood of an in vivo state, the perturbations of stresses and strains are related by linear, anisotropic, tensor equations involving three elastic constants: the incremental Young's modulus in the circumferential direction Y , that in the longitudinal direction Y_zz, and the cross modulus Y_z Over a 24 h period, changes of Y between 164 and 187 kN/m² Y_zz between 64 and 92 kN/m² and Y _z between 61 and 88 kN/m² are statistically insignificant. © 2001 Biomedical Engineering Society. PAC01: 8719Rr, 8719Uv     

HMGB1 enhances smooth muscle cell proliferation and migration in pulmonary artery remodeling

HMGB1 is a necessary and critical mediator of acute lung injury and can act as a chemoattractant and anti-apoptosis factor in injury or repair in diseases. In this study we sought to determine whether HMGB1 is involved in the remodeling of pulmonary artery and investigate the mechanism. A rat model of pulmonary artery remodeling was successful induced with LPS infusion and the increasing of pulmonary arteries media was obviously inhibited in rats treated with thrice inject of HMGB1 neutralizing antibody. The percent of areas of tunica media to total artery wall was (0.53±0.15), (0.81±0.10) and (0.59±0.11) in control, LPS and antibody group respectively (p<0.05). Meanwhile, treatment with HMGB1 neutralizing antibody not only decreased the level of HMGB1 mRNA and protein significantly, but inhibited the expression of PCAN and Bcl-2 as well. On the contrary, Bax, a gen which represented the apoptosis, revealed an absolutely reversed trend to Bcl-2 in pulmonary arteries. Experiments in vitro showed that HMGB1 could stimulate the proliferation of hPASMC in MTT test and increase the number of migrated cells in a concentration-dependent manner in chemotaxis assay using modified Boyden chambers. In conclusion, data from this study support the concept that HMGB1 is involved in the remodeling of pulmonary artery by enhancing proliferation and migration of smooth muscle cell. Inhibiting HMGB1 may be a new target to deal with the remodeling of pulmonary artery.     

CTGF在烟雾暴露大鼠肺血管中的表达及其与肺血管重建的关系

目的：探讨烟雾暴露致大鼠肺血管重建中结缔组织生长因子(CTGF)表达的变化及意义。方法：24只大鼠随机分为对照组、烟雾暴露1、2和3月组，HE染色观察肺血管重建，天狼猩红染色检测胶原增殖，免疫组化观察CTGF在肺动脉中的表达，RT-PCR检测肺动脉CTGFmRNA表达。结果：随烟雾暴露时间延长，肺动脉管壁面积/管总面积(WA%)、胶原沉积、CTGFmRNA和蛋白表达呈时间依赖性增加（组间P<0.01）。CTGF表达与WA%呈正相关。结论：大鼠烟雾暴露后早期即出现肺血管重建，且随时间延长逐渐加重，CTGF在肺动脉中的表达逐渐升高，可能在此过程中起重要作用。     

The emigration of lymphocytes from Peyer's patches in sheep

The magnitude of the output of lymphocytes from Peyer's patches (PP), the morphology of the lymphocytes and their route of exit from PP has been examined in sheep. An extracorporeal perfusion system was used to selectively label a 3-4 m length of the terminal ileum of lambs at 6-10 weeks of age (the mesenteric lymph nodes had previously been excised from most lambs). This part of the intestine contains about 80% of the total PP tissue in a lamb and most of the lymphoid cells in the perfused tissue were within the PP. During a 10 min labeling period, fluorescein isothiocyanate (FITC) was added to the perfusate to label all the cells in the perfused tissues and [3H]thymidine [(3H]dThd) was added at the same time to label only those cells in the S-phase of the cell cycle. The unincorporated label was then washed from the perfused tissues, the normal blood circulation was reestablished and the lamb allowed to recover from anesthesia. It was established that the labeling was restricted to the perfused tissue and therefore that any labeled cells subsequently found elsewhere in the animal must have emigrated from the terminal ileum. During the 24 h after perfusion 1.4 X 10(9)-3.9 X 10(9) lymphoid cells (i.e. FITC labeled) left the perfused tissues via the lymph; 12-19% of these cells were either in the process of dividing or less than 24 h old (i.e. [3H] dThd labeled). The majority of the labeled cells probably came from the PP and most were classified as small lymphocytes although the [3H] dThd labeled population included a high proportion of large lymphocyte and lymphoblasts especially during the early hours after the perfusion. The labeled lymphocytes entered the blood in substantial numbers which increased linearly with time so that by 24 h about 7% of the lymphocytes in the blood were fluorescent. The numbers of newly produced cells began to increase rapidly in the blood only during the 12 h to 24 h period. The number of labeled cells in the blood was reduced by about 95% when the lymph from the perfused tissues was drained from the lamb during the experiment. This result provides clear evidence that the vast majority of all of the cells that leave the PP do so via the lymph and not via the blood.     

Pulmonary artery remodeling and pulmonary hypertension after exposure to hyperoxia for 7 days. A morphometric and hemodynamic study.

This study shows by morphometric and hemodynamic techniques that exposure to hyperoxia at normobaric pressure causes rapid structural remodeling of rat pulmonary arteries and pulmonary hypertension. After 7 days of 90% O2, pulmonary artery cross-sectional area is reduced by a striking loss of intraacinar arteries (control, 13 +/- 1 sq mm; exposed, 8 +/- 1 sq mm; P less than 0.001), the ratio of arteries to alveoli being 4:100 in control rats and 2.5:100 after hyperoxia. The lumen of preacinar and intraacinar arteries is narrowed by a reduction of vessel external diameter (ED) and an increased medial wall thickness (MT). There is a significant reduction in the percent medial thickness [( 2 X 100 X MT]/ED) in both regions. The proportion of muscular and partially muscular intraacinar arteries increases at the expense of nonmuscular ones (P [chi 2] less than 0.01), and fully muscular arteries appear in the alveolar wall where they are not normally found. Intimal thickening occurs in 19% of alveolar duct and 34% of alveolar wall nonmuscular arteries. Right ventricular hypertrophy occurs, the ratio of the left ventricle plus the septum to the right ventricle being significantly reduced (control, 4.07 +/- 0.26; exposed, 3.23 +/- 0.10; P less than 0.02). After 3 days of 87% O2, pulmonary artery pressure is still normal (17.0 +/- 0.9 mmHg) but after 7 days it is significantly increased (26.2 +/- 0.9 mmHg; P less than 0.01), as is pulmonary vascular resistance (control, 0.033 +/- 0.003; exposed, 0.065 +/- 0.015 U/kg; P less than 0.05). Return to air breathing (after 7 days at 87% O2) causes pulmonary vasoconstriction and a further rise of the pulmonary artery pressure (to 38.3 +/- 3.3 mmHg after 60 minutes).     

Tissue remodeling of rat pulmonary artery in hypoxic breathing. I. Changes of morphology, zero-stress state, and gene expression

The remodeling of the pulmonary arterial tissue in response to a step change of the oxygen concentration in the gas in which a rat lives was recorded as function of time and function of O₂ concentration. Three steps of changing from 20.9% to 17.2%, 13.6%, and 10% O₂ were imposed. Earlier work in our laboratory has shown that pulmonary arterial tissue remodeling is significant in the first 24 h after a step change of oxygen tension. Hence we made measurements in this period. Furthermore, data were obtained for tissue remodeling of circumferential and axial lengths of the pulmonary arteries. We recorded the activities of gene expressions in the lung tissues by microarray, determined the dose response curves of gene expression in the homogenized whole lungs with respect to four levels of O₂ concentration, and obtained the time courses of gene expression in the lung parenchyma in 30 days after a step decrease of O₂ concentration from 20.9% to 10%. We would like to suggest that the correlation of gene expression with physiological function parameters, i.e., time, O₂ tension, blood pressure, opening angle, wall thicknesses, etc., is the way to narrow down the search for specific genes for specific physiological functions. © 2001 Biomedical Engineering Society. PAC01: 8719Uv     

The evolution and involution of Peyer's patches in fetal and postnatal sheep

The Peyer's patches (PP) of sheep have a number of important anatomical features and functional characteristics which are similar to tissues that have been classified as primary lymphoid organs. The prenatal maturation of PP occurs in the absence of any antigenic stimulus as immunogenic molecules are not normally encountered by the sheep fetus. Primordial PP were first detected in the small intestine of fetal sheep at about 60-days gestation; lymphoid follicles were present by 75-days gestation and vigorous lymphopoiesis was occurring in these follicles by 100 days. From 120-days gestation until birth, at about 150 days, the PP follicles were histologically mature and they had the greatest density of proliferating lymphoid cells found anywhere in the body. The total number of PP and their constituent follicles had developed before birth when there were 25-40 discrete PP in the jejunum and proximal ileum and one single continuous PP in the terminal ileum. There was no evidence of any change in the rate of growth of the PP follicles at birth which could be related to the advent of the first antigens in the gut. The total weight of PP tissue was greater than any other single lymphoid tissue by about 6 weeks after birth weighing around 120 g or about 1.2% of the body weight; about 50-60 g of the PP tissue was calculated to be lymphoid tissue. At this time the ileocecal PP (IPP) extended 2.5 m along the terminal ileum and accounted for about 90% of the total mass of PP. From about 12 weeks after birth the IPP began to involute and only a few PP follicles remained in this region of the intestine by 18 months of age. Follicles in PP in other parts of the small intestine remained and continued to produce lymphocytes throughout the life of the animal. PP contain a number of anatomically and functionally distinct lymphoid compartments that could play different roles in the body's immune defense. Explicit in most theories on the function of PP is the notion that antigenic stimulation is the cause of the lymphopoiesis in the follicles; our results do not support this view. Instead they suggest that the follicles in the PP of sheep may play a role similar to that played by the bursa of Fabricius in birds.     

Vascular remodeling in pulmonary hypertension

Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.     

The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction

Regeneration of the damaged myocardium is one of the most challenging fronts in the field of tissue engineering due to the limited capacity of adult heart tissue to heal and to the mechanical and structural constraints of the cardiac tissue. In this study we demonstrate that an engineered acellular scaffold comprising type I collagen, endowed with specific physiomechanical properties, improves cardiac function when used as a cardiac patch following myocardial infarction. Patches were grafted onto the infarcted myocardium in adult murine hearts immediately after ligation of left anterior descending artery and the physiological outcomes were monitored by echocardiography, and by hemodynamic and histological analyses four weeks post infarction. In comparison to infarcted hearts with no treatment, hearts bearing patches preserved contractility and significantly protected the cardiac tissue from injury at the anatomical and functional levels. This improvement was accompanied by attenuated left ventricular remodeling, diminished fibrosis, and formation of a network of interconnected blood vessels within the infarct. Histological and immunostaining confirmed integration of the patch with native cardiac cells including fibroblasts, smooth muscle cells, epicardial cells, and immature cardiomyocytes. In summary, an acellular biomaterial with specific biomechanical properties promotes the endogenous capacity of the infarcted myocardium to attenuate remodeling and improve heart function following myocardial infarction.     

Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats

Pulmonary hypertension is responsible for significant mortality and morbidity among newborns and infants. The pathology is characterized by pulmonary vascular remodeling with medial hypertrophy and adventitial thickening, leading to decreased gas exchange. Since it is unknown if these abnormalities are reversible, we analyzed these vascular changes in pulmonary hypertensive rats. Exposure of rats to hypobaric hypoxia for 4 weeks induced clinical signs of pulmonary hypertension, such as increased right ventricular systolic pressure, increased right ventricular weight and considerable pulmonary vascular remodeling. The vascular changes were associated with the expression of Non -Muscle Myosin Heavy Chain B in the pre-acinar vessels and an increased expression of alpha Smooth Muscle Actin, Smooth Muscle Myosin Heavy Chain 2 and Calponin in the intra-acinar vessels. The right ventricular systolic pressure and right ventricular weight gradually decreased after specific periods of recovery in normoxia, although this reversal did not reach baseline levels after six weeks at normoxia. However, the cellular changes in the pulmonary vasculature were completely reversed. Development of pulmonary hypertension is associated with an increase of synthetic perivascular cells in the pre-acinar arteries and an aberrant differentiation of perivascular cells in the smallest intra-acinar arteries. These cellular and structural changes in the pulmonary vasculature are completely reversible after recovery in normoxia.     

Primary pulmonary artery leiomyosarcoma.

Primary pulmonary artery sarcomas are uncommon neoplasms with up to 20% of cases being leiomyosarcomas. In many instances, the diagnosis is difficult and delayed. We report the case of a 75-year-old male who presented with symptoms suggestive of recurrent pulmonary thromboemboli, in which a primary leiomyosarcoma of the pulmonary artery was successfully removed surgically. Three years after surgery, the patient is well and with no evidence of recurrence or metastatic disease.     

The effect of antigen on the development of Peyer's patches in sheep

The proposition that the development of Peyer's patches (PP) is influenced by antigenic stimulation has been examined in sheep. Terminal lengths of ileum containing about half of the ileocecal PP were isolated from the intestinal tracts of fetal lambs during the last month before birth. Antigen was injected into some of these segments and the subsequent development of the PP studied before and after birth. The injection of either killed B. abortus, ferritin or maternal colostrum into the lumens of the isolated ileal segments did not cause premature growth of the PP follicles, nor did it effect the content of lymphoblasts in them. In contrast, the injection of these antigens into the isolated segments caused the development of germinal centers and plasma cells in the regional mesenteric lymph nodes. Plasma cells also appeared in the lamina propria along the intestinal tract in response to these antigens. These results provided experimental evidence that lymphopoiesis in the follicles of the PP of fetal lambs is not dependent on antigen. The PP in ileal segments that were not injected with antigen and had no contact with antigen subsequently grew at the normal rate before and for the first 2 weeks after birth; after this the growth of the follicles became significantly slower than normal. The follicles in these isolated ileal segments had almost completely disappeared by 3-4 months of age, whereas the follicles in the normal functional ileum did not undergo involution until around 15 months of age. The premature involution in the PP in the isolated segments was prevented by reconnecting the segment to the functional intestinal tract before 3 months of age.     

Two types of sheep Peyer's patches: location along gut does not influence involution.

In sheep, and some other species, there is evidence of two types of Peyer's patches (PPs), the ileal PP, which extends 150 cm along the terminal ileum, and the jejunal PPs distributed throughout the rest of the small intestine. The two types differ significantly in their histology, ontogeny and the extent of lymphocyte traffic. Another intriguing difference is that the ileal PP involutes about the time of puberty whereas the jejunal PPs function throughout life. This study shows that the differences in PP lifespan is not related to their specific location in the small intestine. Surgery was done at 1-2 months of age to transpose lengths of ileal PP into the jejunum, also, PP-containing lengths of jejunum were transposed into the midst of the ileal PP. Examination at age 12-16 months showed that ileal PP transposed into jejunum had involuted at the same rate as normally sited ileal PP. Also, jejunal PPs transposed into the ileum had not involuted unlike the surrounding ileal PP. It was concluded that the difference in lifespan of the two PPs were not related to the local microenvironment created by gut function, but may be inherent to the PP itself.     

Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension

Remodeling of the pulmonary arteries is a common feature among the heterogeneous disorders that cause pulmonary hypertension. In these disorders, the remodeled pulmonary arteries often demonstrate inflammation and an accumulation of pulmonary artery smooth muscle cells (PASMCs) within the vessels. Adipose tissue secretes multiple bioactive mediators (adipokines) that can influence both inflammation and remodeling, suggesting that adipokines may contribute to the development of pulmonary hypertension. We recently reported on a model of pulmonary hypertension induced by vascular inflammation, in which a deficiency of the adipokine adiponectin (APN) was associated with the extensive proliferation of PASMCs and increased pulmonary artery pressures. Based on these data, we hypothesize that APN can suppress pulmonary hypertension by directly inhibiting the proliferation of PASMCs. Here, we tested the effects of APN overexpression on pulmonary arterial remodeling by using APN-overexpressing mice in a model of pulmonary hypertension induced by inflammation. Consistent with our hypothesis, mice that overexpressed APN manfiested reduced pulmonary hypertension and remodeling compared with wild-type mice, despite developing similar levels of pulmonary vascular inflammation in the model. The overexpression of APN was also protective in a hypoxic model of pulmonary hypertension. Furthermore, APN suppressed the proliferation of PASMCs, and reduced the activity of the serum response factor-serum response element pathway, which is a critical signaling pathway for smooth muscle cell proliferation. Overall, these data suggest that APN can regulate pulmonary hypertension and pulmonary arterial remodeling through its direct effects on PASMCs. Hence, the activation of APN-like activity in the pulmonary vasculature may be beneficial in pulmonary hypertension.     

Continuous air embolization into sheep causes sustained pulmonary hypertension and increased pulmonary vasoreactivity.

Baseline pulmonary arterial, left atrial and systemic artery pressures, cardiac output, and lung lymph flow were measured in seven chronically catheterized sheep before continuous air embolization into the pulmonary artery, which caused a two-to-threefold increase in pulmonary vascular resistance (PVR) for 12 days. Air embolization was discontinued on days 4, 8, and 12 and hemodynamic measurements were repeated. Thromboxane B2, 6-keto-PGF1 alpha, and protein were measured in lung lymph and blood plasma on days 0, 4, 8 and 12. Air embolization caused an acute, sustained rise in pulmonary artery pressure and PVR (baseline, 3.68 +/- 0.21; air, 8.32 +/- 0.62, mean +/- SE). By day 4, PVR was increased significantly even when air flow was interrupted (5.97 +/- 0.72) and by day 12, it was almost twice baseline; pulmonary artery pressure also remained elevated (baseline, 19 +/- 1 cm H2O; day 12, 31 +/- 3). Pulmonary vasoreactivity to PGH2-A was significantly increased on days 4, 8, and 12 (day 12, 285 +/- 41% of baseline response). Lung lymph flow, protein, and thromboxane clearance were increased throughout the study while clearance of 6-keto-PGF1 alpha was increased at day 4 and falling by day 8. At autopsy, morphometric analysis of the barium-injected pulmonary arterial bed revealed striking structural remodeling, extension of muscle into smaller arteries than normal: decreased peripheral arterial filling, increased medial thickness, and dilated large pulmonary arteries. Continuous air embolization into sheep causes the structural and functional changes of chronic pulmonary hypertension accompanied by increased pulmonary vasoreactivity to a bolus of PGH2-A. The abrupt onset of the sustained elevation in PVR induced by air embolization may account for the severity of the structural remodelling, particularly for the increased medial thickness.     

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.