In vivo fluorescence-mediated tomography for quantification of urokinase receptor-dependent leukocyte trafficking in inflammation.

BACKGROUND: Inflammation is characterized by leukocyte recruitment. Macrophages and neutrophils contribute to tissue damage and organ dysfunction. Modulating leukocyte invasion can protect from these adverse effects. Leukocyte recruitment critically depends on the urokinase-type plasminogen activator receptor (u-PAR). We here use a novel technique to longitudinally quantify cell trafficking in inflammatory models in live animals. METHODS: Near-infrared fluorophore-labeled leukocytes were adoptively transferred to mice with thioglycollate peritonitis to study leukocyte trafficking to sites of inflammation. Macrophage and neutrophil trafficking was followed with three-dimensional fluorescence-mediated-tomography. u-PAR-/- and wild-type macrophage recruitment was studied by cross-over adoptive cell transfer to elucidate the role of leukocytic versus u-PAR expressed on other cells. Endotoxic shock-induced pulmonary inflammation was used to study u-PARs role for pulmonary neutrophil recruitment. RESULTS: Mice experiencing peritonitis showed a significant increase in mean fluorescence intensity because of enhanced macrophage (315%, n=9-10), P<0.05) or neutrophil (194%, n=6, P<0.02) recruitment. Fluorescence-mediated-tomography uncovered a macrophage recruitment defect in the peritonitis model for u-PAR-/- mice (147% of baseline) compared with control mice (335% of baseline, n=8-9, P<0.05). When u-PAR-/--macrophages were transferred to wild-type mice fluorescence intensity increased to 145% while wild-type macrophage transfer into u-PAR-/- resulted in 192% increase compared with baseline (n=6, P<0.05). Reduced neutrophil recruitment in pulmonary inflammation in u-PAR-/- mice was accompanied by improved pulmonary gas exchange. CONCLUSION: Using noninvasive in vivo fluorescence-mediated tomography to image leukocyte recruitment in inflammatory mouse models, we describe a novel macrophage recruitment defect in u-PAR-/- mice. Targeting u-PAR for modulation of leukocyte recruitment is a promising therapeutic strategy to ameliorate leukocyte induced tissue damage.

Intravenous sphingosylphosphorylcholine protects ischemic and postischemic myocardial tissue in a mouse model of myocardial ischemia/reperfusion injury.

HDL, through sphingosine-1-phosphate (S1P), exerts direct cardioprotective effects on ischemic myocardium. It remains unclear whether other HDL-associated sphingophospholipids have similar effects. We therefore examined if HDL-associated sphingosylphosphorylcholine (SPC) reduces infarct size in a mouse model of transient myocardial ischemia/reperfusion. Intravenously administered SPC dose-dependently reduced infarct size after 30 minutes of myocardial ischemia and 24 hours reperfusion compared to controls. Infarct size was also reduced by postischemic, therapeutical administration of SPC. Immunohistochemistry revealed reduced polymorphonuclear neutrophil recruitment to the infarcted area after SPC treatment, and apoptosis was attenuated as measured by TUNEL. In vitro, SPC inhibited leukocyte adhesion to TNFα-activated endothelial cells and protected rat neonatal cardiomyocytes from apoptosis. S1P3 was identified as the lysophospholipid receptor mediating the cardioprotection by SPC, since its effect was completely absent in S1P3-deficient mice. We conclude that HDL-associated SPC directly protects against myocardial reperfusion injury in vivo via the S1P3 receptor.

Lidocaine protects from myocardial damage due to ischemia and reperfusion in mice by its antiapoptotic effects.

BACKGROUND: Perioperative myocardial ischemia poses a vital threat to surgical patients. Means to protect postischemic myocardium are clinically not available. Lidocaine has been demonstrated to exert antiinflammatory pleiotropic effects. The authors set out to test if lidocaine protects ischemic myocardium from reperfusion injury. METHOD: A mouse model of transient coronary artery ligation (30 min) and reperfusion (24 h) was used with animal care committee approval. Infarct size and area-at-risk were determined. Leukocyte recruitment was quantified on immunohistochemical stainings. Apoptosis was assessed using enzyme-linked immunosorbent assay to detect histone modifications and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Lidocaine effects on leukocyte-endothelial interactions were assessed in vitro by using a parallel-plate flow chamber or static adhesion assays. RESULTS: Infarct size per area-at-risk was reduced by 27% in mice treated with a lidocaine bolus (1 mg/kg) before a continuous infusion (0.6 mg . kg(-1) . h(-1)) during ischemia (P < 0.005). Neutrophil density in the infarct and periinfarct zone was not reduced by lidocaine, although the size of the infiltrated area was. Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cardiomyocytes and endothelial cells were significantly reduced in the periinfarct zone by lidocaine. In vitro, no effect on leukocyte rolling or firm adhesion to resting or activated endothelium was demonstrable. In vitro, lidocaine reduced cardiomyocyte apoptosis induced by hypoxia and reoxygenation (3h/1h) significantly. Infarct size and in vitro cardiomyocyte apoptosis were likewise reduced when lidocaine bolus and infusion were administered after the ischemic insult. CONCLUSION: Lidocaine exerts cardioprotective effects when administered before or after the ischemic insult. This effect is mediated through an antiapoptotic and not through an antiinflammatory pathway and may be therapeutically exploitable.

High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor.

BACKGROUND: All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport-independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. METHODS AND RESULTS: In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by approximately 20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P3-deficient mice. CONCLUSIONS: Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P3-mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.

["... that progress in anatomy is most likely to occur when its problems include the study of growth and function, as well as of structure". about the anatomy and physiology of Ernst Heinrich Weber (794-1878 and Wilhelm His (1831-1904) his successor in the department of anatomy at the University of Leipzig]. / "... that progress in anatomy is most likely to occur when its problems include the study of growth and function, as well as of structure". Uber den Anatomen und Physiologen Ernst Heinrich Weber (1795-1878) und uber Wilhelm His (1831-1904), seinen Nachfolger auf dem Lehrstuhl für Anatomie an der Universität Leipzig.

The Leipzig anatomist and physiologist Ernst Heinrich Weber had introduced physiological thinking in anatomy and exact methods of mathematical physics to the study of the functioning of the body making him the founder of a physically orientated physiology. But he would not have been that excellent physiologist without being a nonetheless distinguished anatomist since he solved his physiological problems usually following function in close relation to structure. Together with his brother Wilhelm Eduard Weber (1804-1891), who later was to become a famous physicist, in their theory of waves he laid the basis for an exact analysis of the movements of fluids in elastic tubes und was the first to apply the basic laws of hydrodynamics to the circulation of the blood. In collaboration with his youngest brother Eduard Friedrich Wilhelm Weber (1806-1871), who worked as a prosector at his institute and together with Wilhelm Weber had studied the mechanics of the walking apparatus, he demonstrated the inhibiting effect of the vagus nerve on the action of the heart. Ernst Heinrich Weber's approach to consider an organ as a whole not neglecting the study of its function set him apart from most of his contemporaries and has characterized the work of the Leipzig anatomists and physiologists since his time. Among those was Wilhelm His from Basle who succeeded him in the chair of anatomy in 1872. On the basis of a systematic analysis of human embryos by means of serial sections and plastic reconstruction His completely reformed the field of embryology and was the first to present a comprehensive treatise on human embryology. The making of modern human embryology was, above all, his achievement. He did not confine himself to mere description but wanted to gain deeper insight into the causal events by developmental-mechanical conceptions. With his detection of the neuroblasts and that they give rise to an axon and later to dendrites His provided the developmental foundations for the neuron-theory.

Attic perfection in anatomy: Bernhard Siegfried Albinus (1697-1770) and Samuel Thomas Soemmerring (1755-1830).

In Albrecht von Haller's history of anatomy (1777), the period of "Anatomes perfectio" starts with Bernhard Siegfried Albinus. This great anatomist from Leyden was convinced of his concept of a "homo perfectus", an ideal which was rooted in philosophy and which he attempted to bring to life in anatomical illustration through a synthesis of objectivity, symmetry and vitality. Over a generation later, this pursuit of perfection stood as a model for Samuel Thomas Soemmerring who strove to emulate Albinus in his own illustrations and text books. Rejecting the naturalistic alternative, he followed Albinus in attempting to visualize the ideal and invariable norm in anatomy--which in his eyes corresponded to ideal beauty--in such a way that all parts of the body were depicted as though they were alive. This classical approach to what Soemmerring called attic perfection in anatomy aimed at a unity stemming from both science and art. While he admired it in Albinus' atlases and writings, the term may be applied to his own works as well. In my article, these aspects are discussed against the background of the alternative naturalistic style in anatomy as championed by Govard Bidloo, Albrecht von Haller and William Hunter.

[Expression of the dignity of organs: the heart, a muscle]. / Redensarten von der Würde eines Organs: Das Herz, ein Muskel.

As the muscular nature of the heart had been recognized and it had become evident that the heart was nothing but a hollow muscle, it lost its position as the centre of man. This became likewise true for its position within the body studied with anatomical and physiological methods as with the notion of the heart being an organ of sensibility, emotions, intellect, and will revealed in a particular "heart language". The dignity of the heart assigned to it from ancient time was treated with contempt as a but empty phrase. When, however, in the various attempts to study its myocardial architecture its highly sophisticated engeneering became evident, the real marvel of the heart was demonstrated engendering even in men and women of science an "element of aesthetic awe". Thus, in a certain sense, the heart has recovered its dignity.

Robert Willis (1799-1878): the works of William Harvey, M. D., London 1847. A bibliographical note.

Robert Willis was one of the early historians of medicine in Great Britain. He is recalled as a biographer and editor of the works of William Harvey. His translation of Harvey's 'Exercitatio de motu cordis et sanguinis in animalibus' of 1628 is appreciated as the standard rendering among all the English versions of this most influential dissertation. Willis' author's copy of 'The Works of William Harvey' with corrections and notes which, however, are not indicative of attempts at a revision of the text is to be found in the Library of the University of Münster at Westphalia in Germany. The book was donated along with 17,000 other books, in the years 1911/12 to the University Library by the German physician Dr Albert Voss who practised in the United States of America.