A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells.
Intravascular injection of adenoviral vectors may result in a toxic and potentially lethal reaction, the mechanism of which is poorly understood. We noted that mice demonstrated a transient change in behavior that was characterized by inactivity and lethargy within minutes after intravenous injection of relatively low doses of adenoviral vectors (including high-capacity gutless vectors). Moreover, immediately after vector injection a significant drop in blood pressure was measured that most probably was caused by the systemic activation of endothelial cells as monitored by detection of phosphorylated Akt/PKB kinase, activated endothelial nitric oxide synthase (eNOS), and nitrotyrosine. The activation of the endothelium was the result of the interaction of viral particles with Kupffer cells, which are resident macrophages of the liver representing the first line of defense of the innate immune system. Surprisingly, the uptake of vector particles by Kupffer cells not only resulted in their strong activation, but also in their nearly complete disappearance from the liver. Our results suggest that the toxicity of intravenously injected adenoviral vectors may be directly linked to the activation and destruction of Kupffer cells.
Schiedner
Gudrun
G
Center for Molecular Medicine (ZMMK), University of Cologne, 50931 Cologne, Germany. Gudrun.Schiedner@medizin.uni-koeln.de
Bloch
Wilhelm
W
Hertel
Sabine
S
Johnston
Marion
M
Molojavyi
Andrei
A
Dries
Volker
V
Varga
Georg
G
Van Rooijen
Nico
N
Kochanek
Stefan
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure; D015777:Eicosanoids / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D011863:Radioimmunoassay; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D015777:Eicosanoids; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse