Peter P. Nawroth

Interleukin-1 inhibits the synthesis of von Willebrand factor in endothelial cells, which results in a decreased reactivity of their matrix toward platelets.

We have studied the influence of recombinant human and murine interleukin-1 (IL-1) on the synthesis and secretion of von Willebrand factor by human endothelial cells. Treatment of endothelial cells with IL-1 caused a decline in the steady-state level of von Willebrand factor mRNA in endothelial cells. This decline resulted in a decreased secretion to the culture medium, a decreased storage of von Willebrand factor in the Weibel-Palade bodies, and a decreased incorporation into the extracellular matrix. As a consequence of the decreased amount of von Willebrand factor in the extracellular matrix we have found a strongly impaired platelet adhesion to these matrices. When the matrices of IL-l-treated cells were incubated with purified von Willebrand factor, their ability to support platelet adhesion was restored. These results suggest that perturbation of endothelial cells by inflammatory mediators like IL-1 results in a decreased adhesion of platelets to the subendothelium owing to a diminished synthesis of von Willebrand factor.

Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis?

Beside many efforts to improve outcome, sepsis is still one of the most frequent causes of death in critically ill patients. It is the most common condition with high mortality in intensive care units. The complexity of the septic syndrome comprises immunological aspects - i.e., sepsis induced immunosuppression - but is not restricted to this fact in modern concepts. So far, exact mechanisms and variables determining outcome and mortality stay unclear. Since there is no typical risk profile, early diagnosis and risk stratification remain difficult, which hinders rapid and effective treatment initiation. Due to the heterogeneous nature of sepsis, potential therapy options should be adapted to the individual. Biomarkers like C-reactive protein and procalcitonin are routinely used as complementary tools in clinical decision-making. Beyond the acute phase proteins, a wide bunch of promising substances and non-laboratory tools with potential diagnostic and prognostic value is under intensive investigation. So far, clinical decision just based on biomarker assessment is not yet feasible. However, biomarkers should be considered as a complementary approach.

Diabetes mellitus Typ 1 und Typ 2

Diabetes mellitus Typ 1 und Typ 2 stellen pathophysiologisch zwei vollig unterschiedliche Entitaten dar. Wahrend der Typ-1-Diabetes durch eine autoimmunebedingte Destruktion der pankreatischen β-Zelle zu einem absoluten Insulinmangel fuhrt und die Therapie in einer moglichst physiologischen Insulinsubstitution besteht, ist der Typ-2-Diabetes eine heterogene, chronisch progressive Erkrankung, die durch Insulinresistenz und defiziente Insulinsekretion auf dem Boden genetischer und erworbener Defekte charakterisiert ist. In Deutschland sind zurzeit 8 Millionen Menschen an einem Typ-2-Diabetes erkrankt, weltweit etwa 200 Millionen. Nach Schatzungen der WHO ist von einer Verdoppelung dieser Zahlen innerhalb der nachsten 25 Jahre auszugehen. Die individuellen und volkswirtschaftlichen Folgen sind dabei betrachtlich: Schon heute mussen in Deutschland uber 25 Milliarden Euro fur die Behandlung und die Folgekosten des Typ-2-Diabetes aufgebracht werden.

Tumor Necrosis Factor/Cachectin and the Modulation of Endothelial Cell Coagulant Properties

The coagulation mechanism is an effector system capable of rapidly and effectively responding to environmental stimuli. In order to play an integral role in the host response in pathophysiologic states, function of the coagulation mechanism must be linked to the host defense. Since the coagulation mechanism is regulated by tonically active, opposing anticoagulant and procoagulant mechanisms, this suggested the following hypothesis: in homeostasis the balance of coagulation mechanisms on the endothelial cell surface should favor anticoagulation, whereas in stimulated states procoagulant activities would predominate. Sepsis, a disease state with multiple abnormalities of intravascular coagulation, provided an opportunity to test this hypothesis. Our question concerned whether a central mediator of the septic state (1,2), Tumor Necrosis Factor/Cachectin (TNF), could induce the coordinate induction of endothelial cell pro-coagulant activity and suppression of anticoagulant mechanism.