Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8056, USA.
Am J Respir Crit Care Med. 2012 Jun 1;185(11):1205-17. doi: 10.1164/rccm.201108-1545OC. Epub 2012 Mar 1.
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, alveolar destruction, and airway and vascular remodeling. However, the mechanisms that lead to these diverse alterations have not been defined.
We hypothesized that IL-18 plays a central role in the pathogenesis of these lesions.
We generated and characterized lung-specific, inducible IL-18 transgenic mice.
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 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.
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.
慢性阻塞性肺疾病（COPD）的特征是慢性炎症、肺泡破坏以及气道和血管重塑。然而，导致这些不同改变的机制尚未明确。
我们假设白细胞介素 18（IL-18）在这些病变的发病机制中起核心作用。
我们生成并表征了肺特异性、诱导型 IL-18 转基因小鼠。
在这里，我们证明了成熟鼠肺中 IL-18 的表达会引发炎症，其特征是 CD4(+)、CD8(+)、CD19(+)和 NK1.1(+)细胞的积累、肺气肿、黏液化生、气道纤维化、血管重塑以及右心室心肌肥厚。我们还证明，IL-18 诱导 I 型、II 型和 17 型细胞因子，抑制 IFN-γ诱导的巨噬细胞、淋巴细胞和嗜酸性粒细胞积聚，同时刺激肺泡破坏和与细胞毒性以及 IL-13 和 IL-17A 相关的基因，诱导黏液化生、气道纤维化和血管重塑。我们还强调了这些反应之间的相互作用，IL-18 通过依赖于 IL-17A 的机制诱导 IL-13，而 I 型和 17 型/2 型反应则相互抑制。
这些研究定义了肺内 IL-18 诱导的炎症、实质、气道和血管改变的范围；强调了这些反应与 COPD 病变之间的相似性；并定义了 I 型、II 型和 17 型反应在产生 IL-18 诱导的病理学中的选择性作用。
