Min-Jong Kang1,* , Je-Min Choi2,3,*, Bo Hye Kim1, Chang-Min Lee1, Won-Kyung Cho1, Gina Choe1, Do-Hyun Kim2,3, Chun Geun Lee1 and Jack A Elias1,4,5
1Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine
2Department of Life Science, Research Institute for Natural Sciences,
3Hanyang Biomedical Research Institute,Hanyang University, Seoul, 133-791, Republic of Korea
4Department of Internal Medicine, Yale University School of Medicine
5Corresponding Author: Jack A Elias
*Equally contributed for the study
Rationale. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, alveolar destruction and airway and vascular remodeling. However, the mechanism(s) that leads to these diverse alterations has not been defined.
Hypothesis. We hypothesized that IL-18 plays a central role in the pathogenesis of these lesions.
Methods. We generated and characterized lung-specific, inducible IL-18 transgenic mice.
Results. Here we demonstrate that the expression of IL-18 in the mature murine lung induces inflammation that is associated with the accumulation of CD4+, CD8+, CD19+ and NK1.1+ cells, emphysema, mucus metaplasia, airway fibrosis, vascular remodeling and right ventricle cardiac hypertrophy. We also demonstrate that IL-18 induces type 1, type 2 and type 17 cytokines with gamma interferon (IFN-γ) inhibiting macrophage, lymphocyte and eosinophil accumulation while stimulating alveolar destruction and genes associated with cell cytotoxicity and IL-13 and IL-17A inducing mucus metaplasia, airway fibrosis, and vascular remodeling. We also highlight interactions between these responses with IL-18 inducing IL-13 via an IL-17A-dependent mechanism and the type 1 and type17/type 2 responses counterregulating each another.
Conclusions. These studies define the spectrum of inflammatory, parenchymal, airway and vascular alterations that are induced by pulmonary IL-18, highlight the similarities between these responses and the lesions in COPD and define the selective roles that type 1, type 2 and type 17 responses play in the generation of IL-18-induced pathologies.
interleukin-18, chronic obstuctive pulmonary disease, airway fibrosis, vascular remodeling, cor pulmonale