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Journal of Endotoxin Research, Vol. 10, No. 6, 393-401 (2004)
DOI: 10.1177/09680519040100060301

Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression

Caroline Oberholzer

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA

Andreas Oberholzer

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA

Sven K. Tschoeke

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA

Rebecca M. Minter

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA

Frances R. Bahjat

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA

Drake LaFace

Canjii Inc., San Diego, California, USA

Beth Hutchins

Canjii Inc., San Diego, California, USA

Lyle L. Moldawer

Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA, moldawer{at}surgery.ufl.edu

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 TNF-{alpha}-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-{alpha}-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 TNF-{alpha} 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 TNF-{alpha} appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-{alpha} 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.

Key Words: Gene therapy • inflammation • apoptosis • cytokine • lipopolysaccharide


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