Decoy gelatin nanoparticles as a novel tool to elucidate the role of NF-kB in Kupffer cells on hepatic ischemia/reperfusion injury

Kupffer cells, the resident macrophages of the liver, play an
important role in host defense and immune system. Moreover, they
are also involved in several pathological conditions, like the
hepatic ischemia/reperfusion injury. The transcription factor NF-kB
is activated during this event. However, to date it was not
possible to evaluate the consequence of this upregulation, as NF-kB
possesses both detrimental and beneficial properties, regarding of
the liver cell type affected. An activation in Kupffer cells is
thought to lead to an increased inflammatory response. This
hypothesis could not be proven in vivo, as a selective inhibition
of NF-kB in Kupffer cells was not possible due to technical
difficulties. In this work, solid nanoparticles made of gelatin
were chosen to deliver NF-kB inhibiting decoy oligonucleotides
exclusively to Kupffer cells in order to block the activation of
NF-kB. Confocal scanning laser microscopy showed selective uptake
of gelatin nanoparticles into the Kupffer cells without affecting
hepatocytes. An increase in NF-kB binding activity during
postischemic reperfusion could be diminished by the delivery of
decoy oligonucleotides to the resident liver macrophages. In
addition, a rise in TNF-alpha mRNA expression assessed by real time
RT-PCR was also reduced, thus providing evidence for the
effectiveness of this selective targeting. Thus, this work
established a novel carrier for a specific Kupffer cell targeting.