bluuebunny/crossref_metadata_2025_split huggingface dataset:
T‐Lymphocytes Contribute to Hepatic Leukostasis and Hypoxic Stress Induced by Gut Ischemia‐Reperfusion
Authors: HORIE YOSHINORI , WOLF ROBERT , CHERVENAK ROBERT P. , JENNINGS STEPHEN R. , GRANGER D. NEIL 
Published: January 2010

ABSTRACTAlthough neutrophils have been implicated in the hepatic injury elicited by gut ischemia/reperfusion (I/R), the contribution of other leukocyte populations to this injury process remains unclear. The objective of this study was to determine whether lymphocytes contribute to gut I/R‐induced microvascular dysfunction and inflammatory responses in the liver. Intravital videomicroscopy was used to monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine nucleotide (NADH) autofluorescence in livers of wild‐type, SCID, and interferon‐γ (IFN‐γ) knockout mice exposed to 15 min of gut ischemia and 1 h of reperfusion. In wild‐type mice, gut I/R elicited significant increases in the number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF‐α levels. All of these responses were profoundly attenuated in SCID mice, while only some of the responses (in the midzonal region) were blunted in IFN‐γ knockout mice. Reconstitution (24 h before ischemia) of the circulating lymphocyte pool with T‐cell enriched splenocytes, but not T‐cell deficient (from nude mice), CD4+ T‐cell depleted splenocytes or splenocytes derived from IFN‐γ knockout mice, allowed the SCID mice to respond to gut I/R in a manner similar to wild‐type mice. Some of the responses were restored following reconstitution with CD8+ T‐cell depleted splenocytes. These findings implicate CD4+ Tlymphocytes and IFN‐γ in the hepatic microvascular dysfunction and inflammatory cell accumulation elicited by gut I/R.
In Vivo Assessment of Synovial Microcirculation and Leukocyte‐Endothelial Cell Interaction in Mouse Antigen‐Induced Arthritis
Authors: VEIHELMANN ANDREAS , HARRIS ANTHONY GUSTAVE , KROMBACH FRITZ , SCHÜTZE ELKE , REFIOR HANS JÜRGEN , MESSMER KONRAD 
Published: January 2010

ABSTRACTObjective: The microcirculation and leukocyte‐endothelial cell interaction in synovial tissue of an inflamed joint are known to play a crucial role in the pathogenesis of rheumatoid arthritis. The aim of this study was to characterize the in vivo changes in the microvasculature and in leukocyte‐endothelial cell interactions in the mouse synovial tissue using intravital fluorescence microscopy in three stages of antigen‐induced arthritis. The expression of E‐ and P‐selectin and ICAM‐1 were also studied using immunohistochemistry.Methods: Antigen‐induced arthritis (AiA) was produced in Balb/c mice. The severity of arthritis at three different phases was quantified using a clinical and histological score. For the intravital fluorescence microscopy measurements, the patella tendon was partially resected for visualization of the intraarticular synovial tissue of the knee joint. The number of rolling and adherent leukocytes, functional capillary density (FCD) and RBC velocity were quantitatively measured in synovial microvessels. Expression of ICAM‐1, E‐ and P‐selectin was assessed by immunohistochemistry.Results: There was a significant increase in the leukocyte rolling fraction in postcapillary venules in the acute phase of AiA (from 0.26 ± 0.05 in controls to 0.45 ± 0.04 8 d after AiA induction). The number of leukocytes adherent to the endothelium was significantly elevated in all phases of arthritis (from 121 ± 27 in controls to 376 ± 62 mm2 63 d after AiA‐induction). Functional capillary density was significantly enhanced in the acute (332 ± 15 cm/cm2) and intermediate phases (320 ± 15 cm/cm2) compared to control values (227 ± 15 cm/cm2). Arthritis resulted in a distinct increase in the expression of ICAM‐1 on the synovial endothelium in all phases of AiA. E‐ and P‐selectin expression were detected only in the acute phase.Conclusion: Our model provides new insights into the microcirculatory changes which occur in the synovial tissue of an arthritic joint.
Quantitative Image Analysis of F‐Actin in Endothelial Cells
Authors: EHRINGER WILLIAM D. , YAMANY SAMEH , STEIER KELLY , FARAG ALY , ROISEN FREDERICK J. , DOZIER ALAN , MILLER FREDERICK N. 
Published: January 2010

ABSTRACTObjective: Filamentous actin (F‐actin) plays a central role in maintaining endothelial barrier function. Thrombin and histamine, two inflammatory mediators that increase endothelial permeability, can alter F‐actin production and distribution. In this study, we use a newly developed image analysis technique to show that these two inflammatory mediators differentially alter F‐actin structure.Methods: Human umbilical vein endothelial cells were grown to confluence and treated with either histamine (1 µM), thrombin (1 µM) or the agonist's vehicle. The endothelium was stained with BODIPY‐phallodin, and digitized images were taken of the treated cells. The digitized images of individual human umbilical vein endothelial cells (HUVEC) were imported into a F‐actin image analysis program (FAAP) and converted to layers, each one‐pixel thick. The program then determined the mean gray level (which corresponded to the amount of F‐actin) in each layer starting from the outside of the cell (layer 1) and progressing in one pixel layer increments towards the center of the cell (layer 32).Results: Both inflammatory mediators increased endothelial F‐actin production, however, the distribution of the actin was different. Thrombin increased the presence of stress fibers, while also decreasing peripheral banding actin. In contrast, histamine had no effect on peripheral actin compared to control, but did increase the presence of F‐actin stress fibers.Conclusions: These results establish that thrombin and histamine alter endothelial F‐actin production in different locations within the cell, which can be quantified using an image analysis program.
The Microcirculation and Inflammation: Site of Action for Glucocorticoids
Authors: PERRETTI MAURO , AHLUWALIA AMRITA 
Published: January 2010

ABSTRACTThe glucocorticoid hormones and their synthetic derivatives are potent suppressors of inflammatory and allergic pathologies. Their widespread efficacy is the result of multiple modes of action occuring predominantly at the level of the microcirculation. Indeed the glucocorticoids interfere with the function of all of the cellular components of the microcirculation associated with an inflammatory response. These agents inhibit vasodilatation of the arteriolar and capillary beds, therefore preventing the increase in blood flow that characterizes the initial stages of the inflammatory response. They also prevent increases in vascular permeability in the capillary and post‐capillary venule, thereby reducing exudate formation. Finally, the glucocorticoids potently suppress leukocyte emigration across post‐capillary venules. However, this promiscuity of the glucocorticods to act at multiple sites also endows this class of drugs with major side effects associated with chronic treatment. We propose that one way to progress forward is to understand better the effects of glucocorticoids within the microcirculation. This may aid identification of specific molecular sites of action and therefore the development of novel glucocorticoid molecules with fewer side effects.
Nitric Oxide Protects Venules Against Histamine‐Induced Leaks
Authors: AL‐NAEMI HAMDA , BALDWIN ANN L. 
Published: January 2010

ABSTRACTObjective: The goal of the present study was to investigate the prophylactic role of nitric oxide (NO) in the mesenteric microvasculature in preventing microvascular leakage subsequent to histamine application, and to evaluate the response of mast cells during these conditions.Methods: Regions of the rat mesenteric microcirculation were flushed free of blood and pretreated with either the nitric oxide donor sodium nitroprusside (SNP 10−6 M) or Hepes‐buffered saline containing 0.5% bovine serum albumin (HBS‐BSA) for 15 minutes, then exposed to histamine (10−3 M) for another three minutes. In another set of experiments, the microvasculature was treated with either histamine (10−3 M) for three minutes or SNP (10−6 M) for 15 minutes. A control group was treated with HBS‐BSA for 15 minutes.Results: The protective role of NO was evaluated by its ability to reduce or prevent histamine‐induced venular leaks. Mesenteric microvessels pretreated with SNP before histamine suffusion showed a significant decrease in both area and number of venular leaks following the perfusion of fluorescein isothiocyanate‐labeled bovine serum albumin (FITC‐BSA). Although SNP pretreatment did not reduce the percentage of mast cells that degranulated in the presence of histamine, it did somewhat reduce the severity of the degranulation.Conclusion: This study demonstrated that nitric oxide availability protects mesenteric venules against histamine‐induced leaks, but does not prevent degranulation of mast cells. Therefore, nitric oxide probably acts directly on venular endothelial cells to prevent leak formation.
Expression of Endothelial Cell Adhesion Molecules in Neovascularized Tissue
Authors: VALLIEN GINA , LANGLEY ROBERT , JENNINGS STEPHEN , SPECIAN ROBERT , GRANGER D. NEIL 
Published: January 2010

ABSTRACTObjective: Recent studies indicate that endothelial cells of newly formed blood vessels are activated and exhibit a distinct phenotype that may influence the responses of these microvessels to an inflammatory stimulus. The objective of this study was to compare the basal and cytokine‐stimulated expression of endothelial cell adhesion molecules in neovascularized tissue to normal (nonproliferating) vascular beds.Methods: The expression of P‐ and E‐selectin, VCAM‐1, ICAM‐1, ICAM‐2, and PECAM‐1 was measured, using the dual radiolabeled mAb technique, in subcutaneously implanted (for 10–15 days) polyurethane sponges, skin, heart, lung, and intestine of male C57BL/6 mice (background).Results: Basal values of PECAM‐1 and ICAM‐2 revealed a low vascular density in the implanted sponge matrices that is comparable to skin. When normalized for vascular surface area (PECAM‐1 or ICAM‐1 expression), the basal level of E‐ and P‐selectin expression was highest in neovascularized sponge and skin. TNF‐α elicited an increased expression of all endothelial CAMs, except PECAM‐1 and ICAM‐2, but the responses were blunted in sponge and skin, relative to other vascular beds.Conclusions: These findings indicate that endothelial cells in newly formed blood vessels exhibit a pattern of basal and cytokine‐induced expression of certain adhesion glycoproteins that is similar to nonproliferating cutaneous vessels.
Possible Steps Involved in the Transition to Stationary Adhesion of Rolling Neutrophils: A Brief Review
Authors: SMITH C. WAYNE 
Published: January 2010

ABSTRACTThe transition from rolling to firm adhesion is a phenomenon frequently observed when neutrophils are interacting with activated endothelium in vitro or in vivo under physiologically relevant shear stress. The mechanisms leading to this activation are poorly understood, though selectin‐dependent tethering and CD18‐integrin‐dependent adhesion are known to be involved. This transition may involve a sequence of interactions that trigger sufficient integrin activation to allow cell arrest under flow. Recent evidence is reviewed in support of the concept that integrin (Mac‐1 and LFA‐1) activation results from signaling that occurs through selectin binding, chemotactic factor stimulation, and, possibly, LFA‐1 binding.
Signal Transduction Pathways in Enhanced Microvascular Permeability
Authors: YUAN SARAH Y. 
Published: January 2010

ABSTRACTWe have been investigating the molecular mechanisms underlying pathophysiological regulation of microvascular permeability on isolated venules and cultured venular endothelial monolayers. Physiological approaches have been employed in combination with molecular analyses to probe the signal transduction pathways leading to enhanced microvascular permeability. A newly developed technique of protein transfection into cells and intact microvessels enables the correlation of functional reactions and signaling events at the molecular level in a direct and specific fashion. The results indicate that inflammatory mediators increase microvascular permeability via intracellular signaling pathways involving the activation of phospholipase C, cytosolic calcium, protein kinase C, nitric oxide synthase, guanylate cyclase, and protein kinase G. In response to the signaling stimulation, complex biochemical and conformational reactions occur at the endothelial structural proteins. Specifically, myosin light‐chain activation‐mediated myosin light‐chain phosphorylation can result in cell contraction. VE‐cadherin and β‐catenin phosphorylation may induce dissociation of the junctional proteins and their connection to the cytoskeleton, leading to a loose or opened intercellular junction. Focal adhesion phosphorylation and redistribution further provide an anchorage support for the conformational changes in the cells and at the cell junction. The three processes may act in concert to facilitate the flux of fluid and macromolecules across the microvascular endothelium.
Heterogeneous Distribution of Tumor Blood Supply Affects the Response to Chemotherapy in Patients with Head and Neck Cancer
Authors: GALMARINI FELIPE C. , GALMARINI CARLOS M. , SARCHI MARÍA I. , ABULAFIA JORGE , GALMARINI DARÍO 
Published: January 2010

ABSTRACTObjective: To evaluate if the heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer.Methods: We treated 25 stage III/IV patients with an intraarterial cisplatinum‐bleomycin regimen. Prior to treatment, a blue dye was injected directly to tumors through the catheter. Well‐stained areas were considered as profusely perfused areas whereas poorly stained areas were considered as poorly perfused areas. Biopsies of both areas of each tumor were taken prior to and after the treatment and the histopathological response was evaluated with the following grading: I, tumor disappearance; II, destruction of some tumor nests; III, no changes.Results: Grade I responses were attained in 13/25 (52%) of profusely perfused areas against 1/25 (4%) of poorly perfused areas (p < 0.001). Moreover, there were significant differences (p < 0.001) in the overall responses: 21/25 (84%) in the profusely perfused areas versus 7/25 (28%) in the poorly perfused areas; and in grade III responses (4/25, 16% vs. 18/25, 72%). To determine a possible correlation between the histopathological responses obtained in profusely perfused and in poorly perfused areas of each tumor, we then calculated the Kendall's tau‐b statistics, obtaining a τ value of 0.279 (p = 0.145). This data indicated that histopathological responses to chemotherapy of profusely perfused and poorly perfused areas were independent in each tumor.Conclusions: Heterogeneity in the distribution of tumor blood supply affects the response to chemotherapy by influencing the intratumoral delivery of therapeutic agents. After the administration of effective doses of anticancer drugs to a tumor, cells in profusely perfused areas receive enough to destroy them while cells in the poorly perfused areas are exposed to lower drug concentrations and, therefore, survive. This phenomenon could explain in part the difficulty in the treatment of human solid tumors.
New Method for Imaging Innervation of the Renal Preglomerular Vasculature. Alterations in Hypertensive Rats
Authors: CASELLAS DANIEL , BOURIQUET NATHALIE , ARTUSO ANNIE , WALCOTT BENJAMIN , MOORE LEON C. 
Published: January 2010

ABSTRACTObjective: To develop a new method for viewing adrenergic innervation along renal preglomerular vessels; to assess nerve densities and vascular lesions along arcuate arteries (ArcA), arcuate arterial branches (ArcB), and interlobular arteries (ILA) in spontaneously hypertensive rats (SHR) and in angiotensin II (AngII) and in NG‐nitro‐l‐arginine methyl ester (l‐NAME) hypertensive rats.Methods: Preglomerular vasculatures were isolated after HCl maceration and were immunostained against synaptophysin, a membrane protein of synaptic vesicles. Lesions were stained with Sudan black. Longitudinal nerve densities and relative frequencies of ArcA, ArcB, and ILA endowed with sudanophilic lesions were assessed separately.Results: Synaptophysin immunostaining revealed the vascular neural plexus. Nerves were adrenergic, as the plexus was destroyed by treatment with 6‐hydroxy dopamine. Vascular lesions were not seen in SHR, and increased nerve density was observed along ArcA and ILA. In l‐NAME‐ and AngII‐hypertensive rats, vascular lesions affected predominantly ArcB and ILA, and nerve density was reduced by 12% and 28% (ArcA), 37% and 31% (ArcB), and by 55% and 34% (ILA), respectively, versus normotensive controls. Endothelin‐1 receptor blockade did not affect AngII‐induced hypertension but prevented both lesion development and reduction of density of the vascular neural plexus.Conclusions: The method we have devised provides a direct en face view of the vascular adrenergic innervation of isolated preglomerular vasculature. Measurements in hypertensive rat models suggest a link between vascular lesions and reduction in nerve density in hypertension. Endothelin‐1 likely plays a key role in mediating both vascular injury and altered vascular nerve density in hypertension.
Microcirculatory Inflammation in Chronic Venous Insufficiency: Current Status and Future Directions
Authors: DURÁN WALTER , PAPPAS PETER J. , SCHMID‐SCHÖNBEIN GEERT W. 
Published: January 2010

ABSTRACTOne of the hallmarks of chronic venous insufficiency (CVI) is an elevated venous pressure. However, no direct link at the cellular and molecular levels between venous hypertension and actual tissue damage in CVI has been established. Evidence for generation of an inflammatory reaction and several molecular alterations in the development of CVI is discussed. Development of experimental models of CVI, analysis of the mechanical tissue stresses in addition to venous hypertension, in combination with systematic studies of clinically stratified and standardized patient‐derived samples is required for molecular description of the pathogenesis of CVI.
Edward H. Bloch, M.D., Ph.D. Pioneer in the Microscopic Study of, and the Microcirculation of, Living Tissues and Organs
Authors: McCUSKEY ROBERT S. 
Published: January 2010

ABSTRACTEdward H. Bloch, M.D., Ph.D., Professor Emeritus of Anatomy, School of Medicine, Case Western Reserve University, died 3 November 2000 in Cleveland, Ohio at the age of 86. Known to his friends as “Maxl,” he will be greatly missed by his friends, colleagues and former students.
Chronic Vasodilation Induces Matrix Metalloproteinase 9 (MMP‐9) Expression during Microvascular Remodeling in Rat Skeletal Muscle
Authors: van GIESON ERIC J. , SKALAK THOMAS C. 
Published: January 2010

ABSTRACTObjective: The process of microvessel growth and remodeling depends on the presence of matrix metalloproteinases (MMPs) in a specific spatial pattern of expression. This study characterizes the spatial distribution of metalloproteinase‐9 (MMP‐9) expression during microvascular remodeling in the rat spinotrapezius muscle.Methods: Female Sprague‐Dawley rats (4 weeks old) were administered the α1‐adrenergic blocker prazosin for 7 days to induce chronic vasodilation and associated increases in capillary and arteriolar density. MMP‐9 expression was analyzed by Western blotting analysis of microdissected regions of muscle and immunolabeling of muscle sections.Results: Capillary density expressed as both capillary‐to‐fiber ratio (C/F) and capillaries per mm2 increased significantly (p < 0.01) due to prazosin administration. Western blotting on microdissected regions of spinotrapezius muscle showed that there was an increase in MMP‐9 expression in prazosin‐treated animals. Additionally, the Western blots showed a presence of the activated form of MMP‐9 in regions of spinotrapezius muscle containing vessels on the order of capillaries and small arterioles. Immunohistochemistry demonstrated that MMP‐9 significantly increased in the muscles of treated animals in areas within the vessel walls of microvessels greater than 20 µm in diameter. However, interstitial MMP‐9 expression did not significantly increase with prazosin administration.Conclusions: These results demonstrate that the expression of MMP‐9 increases during in vivo microvascular remodeling in adult skeletal muscle. The MMP‐9 expression is limited to larger (>20‐µm diameter) microvessels, suggesting a role for MMP‐9 in the remodeling of such vessels during prazosin‐induced vasodilation and the subsequent capillary proliferation.
Mechanisms of Leukocyte Sequestration in Inflamed Lungs
Authors: DOERSCHUK CLAIRE M. 
Published: January 2010

ABSTRACTThe lungs are an important site of host defense. The capillary blood contains an increased concentration of neutrophils and other leukocytes compared with large vessels, due to the structure of the pulmonary capillary bed, the diameter of spherical leukocytes, and their poor deformability compared with erythrocytes. During inflammation within the distal airways, neutrophils sequester within the pulmonary capillaries and emigrate into the parenchyma. This sequential process involves complex events regulating interactions between mechanical and adhesive properties of both neutrophils and endothelial cells. Initial changes in the cytoskeleton may stiffen the neutrophils and prevent them from deforming, while subsequent dynamic cytoskeletal remodeling of neutrophils and endothelial cells results in crawling and transendothelial migration. Emigration of neutrophils can occur through at least two adhesion pathways: one that requires the CD11/CD18 adhesion complex and one that does not. Which pathway is selected is determined by the stimulus and the signaling pathways that are initiated. Migration through the alveolo‐capillary wall is also highly regulated. Neutrophils released from the bone marrow traffic first through the pulmonary microvasculature, and the phenotype of these newly released neutrophils impacts pulmonary host defense. The many recent studies underline the complexity of neutrophil responses and host defense and the uncertainties of our knowledge.
Tetraspanins and Intercellular Interactions
Authors: YÁÑEZ‐MÓ MARÍA , MITTELBRUNN MARÍA , SÁNCHEZ‐MADRID FRANCISCO 
Published: January 2010

ABSTRACTThe superfamily of tetraspanins comprises a group of polypeptides with four transmembrane domains that form large supramolecular structures in the plasma membrane through their associations to multiple integral membrane proteins. They are involved in homo‐ and heterotypic intercellular interactions in different processes such as hematopoiesis, lymphocyte activation, cancer metastasis, and fertilization. Intercellularly located tetraspanins regulate the juxtacrine activity of growth factors, cell fusion, and myelin formation. On the other hand, in motile cells they relocalize from cell‐cell junctions to actin‐based structures such as filopodia or growth cones and regulate cell motility in wound healing and angiogenesis processes.
Migration of Leukocytes across Endothelial Junctions: Some Concepts and Controversies
Authors: MULLER WILLIAM A. 
Published: January 2010

ABSTRACTThis article is not meant to be a comprehensive review of leukocyte migration or endothelial cell junctions. Rather, I have chosen some aspects of inflammation that might be of general interest to vascular biologists and have focused on the structural and molecular elements of the endothelial junction involved in these processes. These are all active (and some controversial) areas of investigation. I have tried to objectively present both sides of any controversies, while stating at the end the general consensus of the field.