Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure

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Abstract
Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 107 particles (P8 particles and increased mortality at 109 particles. Improved survival after administration of 107 particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100–300 pg/g wet wt). In contrast, mortality after administration of 109 particles was associated with markedly elevated IL-10 expression, both in the lung (10 000–70 000 pg/g wet wt) and systemically (1000–3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFα). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.