Altersabhängige Modulation der Endotoxin-induzierten Schädigung der Rattenleber durch Granulozyten-Kolonie-stimulierenden Faktor (G-CSF) [article]

Sascha Pradarutti, Universität Des Saarlandes, Universität Des Saarlandes
2008
Altersabhängige Modulation der Endotoxin-induzierten Schädigung der Rattenleber durch Granulozyten-Kolonie-stimulierenden Faktor (G-CSF) als Dissertationsschrift zur Erlangung des Grades eines Doktors der Medizin an der Universität des Saarlandes 2007 vorgelegt von Sascha Pradarutti geboren am 02.04.1975 in Cochem In Dankbarkeit meiner Mutter gewidmet. Endotoxinämie im Alter ist durch eine erhöhte Zytokin-Freisetzung charakterisiert, wohl mit der Konsequenz einer stärkeren Beeinträchtigung der
more » ... einträchtigung der Mikrozirkulation und Parenchymintegrität der Leber. Vorbehandlung durch G-CSF ist in der Lage, bei jungen und ausgewachsenen, nicht aber bei alten Tieren die systemisch-inflammatorische Antwort auf Endotoxin und damit die Hepatotoxizität wirksam zu reduzieren. Bei alten Patienten sollte somit die Indikation zur Gabe von G-CSF zur adjuvanten Therapie der Sepsis kritisch diskutiert werden. Abstract 4 2. Abstract 2.1. Age-associated differences in endotoxemic rat liver injury and its modulation by granulocyte-colony stimulating factor Sepsis is a frequent clinical picture and despite of all progress in modern medicine is still afflicted with high morbidity and mortality. The clinical observation that sepsis-related morbidity and mortality increases with age clearly gains importance because of the changing age composition of our society. Granulocyte-colony stimulating factor (G-CSF), known as a hematopoetic growth factor, has been recognized at the beginning of the 90s as an immuno-modulating agent and is used meanwhile adjuvant in the therapy of sepsis. Although protection could be observed by G-CSF in animal studies with endotoxemia, it is still unclear, if immuno-modulation with G-CSF is also effective in aged animals. Hence it has to be clarified, if G-CSF is protective in dependence to age with systemic endotoxemia. We examined this with the use of an age-graded animal model with rats of 3, 12 and 24 months on the basis of systemic cytokine production and hepatic microvascular injury. Animals of all age groups received endotoxin (10 mg / kg i.v.) and, randomised 1 h before endotoxin, either G-CSF (200 µg / kg i.v.) or inert fluid. Intravital fluorescence microscopic analysis and sampling of blood was performed 6 hours after exposure to endotoxin. In contrast to other organ systems the normal aging process of the liver is known only insufficiently. Therefore, we have investigated in a separate study physiological changes in livers of rats of different age (1 month, 3, 12 and 24 months) using high resolution multifluorescence in vivo microscopy. It seemed that already at 1 month of age the liver attained its full size and functional capacity, as assessed by relative organ weight and hepatic bile flow. Survey of liver architecture revealed a progressive growth of lobular area with postsinusoidal venules exhibiting a proportional increase in length, diameter and intervascular distance till the age of 12 to 24 months. With respect to the 3.5-to 4-fold increase of lobular units, the minor reduction of sinusoidal density to 87% during ageing strongly implies the recruitment and formation of new sinusoidal microvessels as contributing mechanism to meet oxygen demand due to overall tissue enlargement. Sinusoidal perfusion rate remained above 98% over the whole lifespan. Leukocytic interaction with the hepatic microvascular endothelium was found within the physiological range in all age groups. Moreover, kinetics of clearance of latex particles as well as lobular distribution of Kupffer cells did not differ between animals of
doi:10.22028/d291-21037 fatcat:ivktypwxtjerjcsbwwjuwzu4zi