AAV6-Mediated IL-10 Expression in the Lung Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder with limited therapeutic options. An aberrant wound healing process in response to repetitive lung injury has been suggested for its pathogenesis, and a number of cytokines including transforming growth factor β1 play pivotal roles in the induction and progression of fibrosis. Thus, the regulation of these pro-inflammatory conditions may reduce the progression of IPF and ameliorate its symptoms in patients. Interleukin-10 (IL-10), a pleiotropic cytokine, exerts anti-inflammatory and anti-fibrotic effects in numerous biological settings. In the present study, we investigated the preventive effects of IL-10 on bleomycin-induced pulmonary fibrosis in mice with the continuous expression of this cytokine via an adeno-associated virus serotype 6 vector. Mice were administered the adeno-associated virus serotype 6 vector encoding mouse IL-10 by intratracheal injection, and osmotic minipumps containing bleomycin were subcutaneously implanted seven days later. Lung histology and the expression levels of pro-inflammatory cytokines and fibrogenic cytokines were then analyzed. In mice exhibiting persistent IL-10 expression on day 35, the number of infiltrated inflammatory cells and the development of fibrosis in lung tissues were significantly reduced. Increases in transforming growth factor β1 and decreases in IFN-γ were also suppressed in treated animals, with changes in these cytokines playing important roles in the pathogenesis of pulmonary fibrosis. Furthermore, IL-10 significantly improved survival in bleomycin-induced mice. Our results provide insights into the potential benefit of the anti-fibrotic effects of IL-10 as a novel therapeutic approach for IPF.

• Authors: Fumio Kurosaki, Ryosuke Uchibori, Yoshihide Sehara, Yasushi Saga, Masashi Urabe, Hiroaki Mizukami, Koichi Hagiwara, Akihiro Kume
• Journal: Human gene therapy (Hum Gene Ther) Vol. 29 Issue 11 Pg. 1242-1251 (11 2018) ISSN: 1557-7422 [Electronic] United States
• PMID: 29598007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Bleomycin
• Interleukin-10
• Collagen

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Bleomycin
• Body Weight
• Collagen (metabolism)
• Dependovirus (metabolism)
• Genetic Therapy
• Genetic Vectors (metabolism)
• Idiopathic Pulmonary Fibrosis (chemically induced, pathology, prevention & control, therapy)
• Inflammation (pathology)
• Interleukin-10 (genetics, metabolism, therapeutic use)
• Lung (metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Survival Analysis