Hämodynamische Charakterisierung eines murinen Sepsis-Modells

The present study´s aim is to establish, validate and hemodynamically characterize a reproducible murine sepsis model. In this process a standardized model to induce a sepsis by cecal legation and perforation (CLP) was first developed. In the second part of our experimental series the model was hemodynamically evaluated. For this, in vivo RR measurements as well as tests on isolated hearts in a Langendorff setup with and without application of pharmacological drugs followed. Our data show that the induction of sepsis by CLP result in the characteristic features of a sepsis like they were observed in septic patients. Furthermore, we observed bacteremia as well as the development of a hyperdynamic phase followed by a hypodynamic state. The results of the survival study indicate that through CLP an induction of a severe sepsis with no survival of septic mice occured. In the sham operated animals no deaths occured. The survival time of septic animals varied between 27 hours and 52 hours after surgery. This difference may depend, amongst others, on the relation of pro-inflammatory to anti-inflammatory cytokines, the produced amount of NO, the quantitative and qualitative differences of the cecum´s pathogens and the state of the physical immunity. In our performed invasive blood pressure measurements we showed that the initial level of the arterial blood pressure of septic mice as well as the levels after application of Dobutamin and Ethylthiourea (ETU) were significantly lower than that of the sham operated mice. NOS blockade with ETU led to an increase in mean arterial blood pressure of septic animals. This suggests that reduced peripheral vascular resistance next to NO is caused through further vasodilatorically acting agents. The cardial dysfunction and the hypodynamic phase indicate a severe manifestation of sepsis and explain the poor outcome of septic mice. This septic cardiomyopathy is refractory to a catecholamine stimulation. The results of our tests on isolated hearts in the Langendorff model demonstrate an obvious septic cardiomyopathy after CLP with reduced left-ventricular contractility. Septic mice initially show an even greater cardiomyopathy than at later time points of examination. This suggests that elevated NO levels and hypoxical stress caused by ischemia after organ preparation during sepsis initially lead to this severe cardiomyopathy. Decreased mVO2 after induction of sepsis shows a dysfunction of the mitochondria with the inhibition of the mitochonfrail respiratory chain. The resulting reduced cellular energy supply might contribute to the cardiomyopathy during a septic shock. By using bradykinine the coronary flow decreased significantly in septic mice compared to the sham operated control group. This susceptibility to eNOS stimulation by bradykinine indicates a high level of eNOS activation secondary to sepsis. After the application of adenosine we observed a significantly lower coronary reserve in the septic animals as well as a lower increase in the coronary flow. This can be attributed to the fact that the basal flow of these animals is already increased by NO. The present study serves as a basis for further therapeutical studies on sepsis treatment in animal tests. Follow-up studies in our laboratory already showed that the survival rate of septic mice improves after statin treatment with the HMG-CoA-reductase inhibitor simvastatin. Furthermore, this study serves as a foundation for the examination of the role of eNOS as well as the meaning of myoglobin as a scavenger of NO during a sepsis with eNOS and myoglobin deficient mice.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2007

Author dc:creator

• Kellinghaus, Jens

Contributors dc:contributor

• Hanrath, Peter

• info:eu-repo/classification/ddc/610
• Sepsis
• CLP
• Hämodynamik
• Stickstoffmonoxid
• NO Synthasen
• Infektion
• Medizin
• hemodynamics
• nitric oxide
• nitric oxide synthase

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123283%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:61643