Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Horn, The Netherlands.
J Immunol. 2010 Jun 15;184(12):7169-77. doi: 10.4049/jimmunol.0900963. Epub 2010 May 19.
Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p<0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p<0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.
瘦素是一种多效性的 I 型细胞因子，最近有研究表明它在慢性阻塞性肺疾病患者和无症状吸烟者的肺部常驻细胞中表达。为了阐明瘦素在慢性阻塞性肺疾病发病机制中的功能作用，我们在香烟烟雾（CS）诱导的肺部炎症模型中测试了瘦素缺陷型 ob/ob 小鼠（C57BL/6）、瘦素受体缺陷型 db/db 小鼠（C57BKS）及其同窝仔鼠。野生型（WT）C57BL/6 小鼠分别暴露于对照空气或 CS 中 4 或 24 周。通过免疫组织化学和实时 PCR 分析肺组织中瘦素的表达。在 4 周 CS 暴露后，评估 WT、ob/ob 和 db/db 小鼠支气管肺泡灌洗液（BALF）和肺组织中的肺部炎症。免疫组织化学分析显示，瘦素在支气管上皮细胞、肺泡细胞、肺泡巨噬细胞和支气管/血管平滑肌细胞中表达。与空气暴露的 WT 小鼠相比，4 和 24 周 CS 暴露增加了支气管上皮细胞和肺泡细胞中的瘦素表达（p<0.05）。4 周 CS 暴露导致 WT、ob/ob 和 db/db 小鼠 BALF 和肺组织中的中性粒细胞、树突状细胞、巨噬细胞和淋巴细胞的积累增加。CS 暴露的 ob/ob 和 db/db 小鼠与 CS 暴露的 WT 小鼠相比，一般显示出更多的中性粒细胞和更少的 CD4+、CD8+和树突状细胞。一致地，CS 暴露的 ob/ob 和 db/db 小鼠的 BALF 中 CXCL1 水平升高（p<0.05）。外源性瘦素给药完全恢复了 ob/ob 小鼠中偏向的炎症特征。这些数据表明，瘦素在 CS 吸入后调节小鼠的固有和适应性免疫中具有重要作用。
