Influence of Recombinant Adenovirus on Liver Injury in Endotoxicosis, and its Modulation by IL-10 Expression
Abstract:
Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNFα-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNFα-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low dose adenovirus administration (105 particles) protects, while high dose adenovirus (1010 particles), is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNFα dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNFα appearance, and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNFα responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.
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