Abstract
Adenovirus and cationic liposome mediated transfer of Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been shown to decrease pro-inflammatory cytokine levels and overall lung inflammation in models of lung transplantation and injury. Limitations to current approaches of IL-10 gene therapy include poor vector delivery methods and pro-inflammatory properties of human IL-10 under certain conditions. We hypothesize that using perfluorochemical (PFC) liquid to deliver the highly homologous viral IL-10 (vIL-10), which is predominantly anti-inflammatory with minimal pro-inflammatory activities, can potentially be a more effective strategy to combat inflammatory lung diseases. In this study, we compare the use of PFC liquid versus aerosolized method to deliver adenovirus encoding the vIL-10 gene (AdvIL-10) in C57Bl6 mice. Detectable vIL-10 levels were measured from bronchoalveolar lavage fluid and lung homogenates at one, four, ten and thirty days after AdvIL-10. Furthermore, we determined if use of PFC liquid could allow for the use of a lower dose of AdvIL-10 by comparing the levels of detectable vIL-10 at different doses of AdvIL-10 delivered +/- PFC liquid. Results showed that PFC liquid enhanced detectable vIL-10 by up to ten fold and that PFC liquid allowed the use of ten-fold less vector. PFC liquid increased detectable vIL-10 in lung homogenates at all time points; however, the increase in detectable vIL-10 in BAL fluid peaked at four days and was no longer evident by thirty days after intratracheal instillation. In summary, this is the first report utilizing PFC liquid to enhance the delivery of a potentially therapeutic molecule, vIL-10. We believe this strategy can be used to perform future studies on the use of the predominantly anti-inflammatory vIL-10 to treat inflammatory lung diseases.
Highlights
Interleukin-10 (IL-10) is a predominantly anti-inflammatory cytokine secreted by activated macrophages, lymphocytes and other cells involved in regulation of the immune response
PFC Liquid Increases Detectable IL-10 To determine the effect of PFC liquid on AdvIL-10 delivery, C57 mice were instilled with 1 × 109 particles of AdvIL-10 with and without PFC liquid
We have demonstrated that use of PFC liquid enhances intratracheal delivery of recombinant AdvIL-10 to rodent lung
Summary
Interleukin-10 (IL-10) is a predominantly anti-inflammatory cytokine secreted by activated macrophages, lymphocytes and other cells involved in regulation of the immune response. One area of research that shows promise is the use of gene transfer-mediated IL-10 expression in the treatment of lung inflammatory diseases. IL-10 gene therapy has been successful at preserving lung integrity and curtailing an over-exuberant inflammatory response in murine lung pneumonia and systemic inflammation models [7,8,9,10]. Inflammatory and immune-mediated lung injury, including obliterative bronchiolitis, remains a major cause of morbidity and mortality for lung transplant recipients. Recombinant adenovirus vector mediated IL-10 expression in lung epithelium was successful at reducing obliterative bronchiolitis in an experimental heterotopic rat lung transplant model[11]
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