Friedrich Grimminger

Simvastatin Inhibits Inflammatory Properties of Staphylococcus aureus α-Toxin

Background—Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuates Staphylococcus aureus &agr;-toxin–induced increase in leukocyte-endothelial interactions during exotoxemia. Methods and Results—The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 &mgr;g/kg) was administered 18 hours before the study. Activation of microcirculation was induced by bolus administration of 40 &mgr;g/kg S aureus &agr;-toxin. Exotoxemia resulted in a significant and time-dependent increase in leukocyte rolling, adherence, and transmigration of leukocytes as well as P-selectin expression on the intestinal vascular endothelium. Pretreatment with simvastatin significantly inhibited exotoxin-induced leukocyte rolling from 71±10 to 14±4.7 cells/min (P <0.01) and adherence from 14±3.5 to 0.4±0.2 cells (P <0.01). In addition, simvastatin pretreatment significantly inhibited transmigration of leukocytes from 10.5±1.2 to 4.2±0.9 (P <0.05) cells. Immunohistochemical detection of endothelial cell adhesion molecule P-selectin showed a 50% decrease in endothelial cell surface expression after simvastatin treatment. Furthermore, simvastatin treatment resulted in enhanced expression of endothelial cell NO synthase III in the intestinal microcirculation. Conclusions—These results demonstrate that simvastatin interferes with exotoxin-induced leukocyte-endothelial cell interactions, which may be relevant in various infectious diseases. Statin treatment may offer a new therapeutic strategy for these clinical conditions.

Staphylococcal α-Toxin Provokes Coronary Vasoconstriction and Loss in Myocardial Contractility in Perfused Rat Hearts Role of Thromboxane Generation

BACKGROUNDnCardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts.nnnMETHODS AND RESULTSnAlpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance.nnnCONCLUSIONSnPurified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.

Additional file 1: Figure S1. of Survival with sildenafil and inhaled iloprost in a cohort with pulmonary hypertension: an observational study

Kaplanâ Meier plots of cumulative transplant-free survival in patients with pulmonary arterial hypertension associated with collagen-vascular disease, idiopathic pulmonary arterial hypertension, and pulmonary arterial hypertension associated with systemic-to-pulmonary shunt. Data are shown for patients who were treated with iloprost followed by addition of sildenafil (iloprost/sildenafil) or sildenafil followed by addition of iloprost (sildenafil/iloprost). (PDF 853Âxa0kb)

Lungenembolie und Lungeninfarkt

Haufigste Ursache einer Lungenembolie (Thromboembolie) ist die Verschleppung von thrombotischem Material aus den tiefen Beinvenen in die pulmonale Strombahn. Sowohl die Lungenembolie als auch die tiefe Beinvenenthrombose stellen aber klinisch meist unerwartete Ereignisse dar, die zu einer Verzogerung der diagnostischen und therapeutischen Masnahmen fuhren konnen und somit entscheidend zu Morbiditat und Letalitat beitragen. Epidemiologische Daten zur Inzidenz der Lungenembolie in Deutschland liegen nicht vor. Ubertragt man jedoch die nordamerikanischen Daten, so kann man von einer Inzidenz von 100.000 bis 150.000 Fallen pro Jahr ausgegangen werden.

Akutes respiratorisches Distress- Syndrom (ARDS)

Die schwere und akut einsetzende Gasaustauschstorung der Lunge charakterisiert das akute respiratorische Distress-Syndrom (ARDS). Diese akute Funktionsstorung der Lunge kann nach unterschiedlichen Auslosern bei jedem Lungengesunden auftreten. Begleitet wird sie von einer pulmonalen Flussigkeitseinlagerung, Storung der pulmonalen Vasomotion und Abnahme der Compliance. Daruber hinaus ist sie unabhangig von Storungen des zentralen Atemantriebs, des Gasflusses in den grosen und kleinen Atemwegen, des Blutflusses in den grosen pulmonalen Gefasen und der linksventrikularen Funktion.

Multiorganinfektionen — komplexe klinisch-infektiologische Krankheiten

Auszug Wir verfügen über ein hochwirksames Arsenal an Antibiotika, wir können auf der Suche nach einem Fokus mit bildgebenden, diagnostischen Verfahren jeden Bereich des menschlichen Körpers darstellen und ggf. punktieren, und doch sind unsere therapeutischen Erfolge bei der Sepsis nach wie vor enttäuschend. Die Letalität der schweren Sepsis und des septischen Schocks liegt unverändert hoch bei 40–70%.

NO pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension

Nitric oxide (NO) is constitutively produced in the lung by NO-synthases. The main cellular sources of lung NO production are the vascular endothelium and the airway epithelia [1, 2]. Adaptation of the perfusion distribution to well ventilated areas of the lung (ventilation/perfusion (V/Q) matching) is mainly regulated by local NO production [3, 4]. NO- synthase activity is regulated on transcriptional and post-translational redox-based modulation level [5]. The common signaling pathway of endogenous vasodilators, such as nitric oxide, prostaglandins, and natriuretic peptides, engage cyclic nucleotides (cAMP and cGMP). The enzymatic source of these second messengers are mainly adenylate-and guanylate-cyclases [6]. PDEs represent a superfamily of enzymes, with PDE1 through PDE11 being currently known, that inactivate cyclic AMP and cyclic GMP, with different tissue distribution and substrate specificities [6, 7]. Depending on their selective profile, PDE inhibitors differentially regulate the activity of cAMP and/or cGMP. Thus, they might be offered as therapeutic tools to augment and prolong prostanoid-and NO-related vascular effects. The efficacy of this approach has been proven in various experimental studies [8, 9]. The most important cyclic GMP degrading phosphodiesterase – PDE5 – is abundantly expressed in lung tissue [7]. The selective PDE5 inhibitor sildenafil has been approved for the treatment of erectile dysfunction [10]. Documented use in numerous otherwise healthy individuals and patients with a variety of underlying diseases sildenafil displayed an excellent safety profile [11].