D'hulst An I, Maes Tania, Bracke Ken R, Demedts Ingel K, Tournoy Kurt G, Joos Guy F, Brusselle Guy G
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium.
Respir Res. 2005 Dec 16;6(1):147. doi: 10.1186/1465-9921-6-147.
Chronic obstructive pulmonary disease is associated with a chronic inflammatory response of the host to chronic exposure to inhaled toxic gases and particles. Although inflammatory cells of both the innate and adaptive immune system infiltrate the lungs in pulmonary emphysema and form lymphoid follicles around the small airways, the exact role of the acquired immune system in the pathogenesis of emphysema is not known.
In this study, wild type Balb/c mice and immunodeficient scid mice--which lack functional B- and T-cells--were exposed to mainstream cigarette smoke (CS) for 5 weeks or 6 months.
Subacute CS-exposure for 5 weeks significantly increased innate inflammatory cells (neutrophils, macrophages and dendritic cells) in the bronchoalveolar lavage (BAL) fluid of wild type mice and scid mice, which correlated with the CS-induced upregulation of the chemokines Monocyte Chemotactic Protein-1, Macrophage Inflammatory Protein-3alpha and KC (= mouse Interleukin-8). Chronic CS-exposure for 6 months significantly increased the number of neutrophils, macrophages, dendritic cells, CD4+ and CD8+ T-lymphocytes in BAL fluid and lungs of wild type mice compared to air-exposed littermates, and augmented the size and number of peribronchial lymphoid follicles. In contrast, neither B-lymphocytes, nor T-lymphocytes, nor lymphoid follicles could be discerned in the lungs of air- or CS-exposed scid mice. Importantly, chronic CS-exposure induced pulmonary emphysema in both wild type animals and scid mice, as evidenced by a significant increase in the mean linear intercept and the destructive index of CS-exposed versus air-exposed animals. The CS-induced emphysema was associated with increased mRNA expression of matrix metalloproteinase-12 in the lungs and increased protein levels of Tumor Necrosis Factor-alpha in the BAL fluid of CS-exposed Balb/c and scid mice compared to air-exposed littermates.
This study suggests that the adaptive immune system is not required per se to develop pulmonary emphysema in response to chronic CS-exposure, since emphysema can be induced in scid mice, which lack lymphoid follicles as well as functional B- and T-cells.
慢性阻塞性肺疾病与宿主对长期吸入有毒气体和颗粒的慢性炎症反应相关。尽管先天性和适应性免疫系统的炎症细胞在肺气肿时会浸润肺部，并在小气道周围形成淋巴滤泡，但获得性免疫系统在肺气肿发病机制中的确切作用尚不清楚。
在本研究中，将野生型Balb/c小鼠和缺乏功能性B细胞和T细胞的免疫缺陷型scid小鼠暴露于主流香烟烟雾（CS）中5周或6个月。
5周的亚急性CS暴露显著增加了野生型小鼠和scid小鼠支气管肺泡灌洗（BAL）液中的先天性炎症细胞（中性粒细胞、巨噬细胞和树突状细胞），这与CS诱导的趋化因子单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-3α和KC（=小鼠白细胞介素-8）的上调相关。与空气暴露的同窝小鼠相比，6个月的慢性CS暴露显著增加了野生型小鼠BAL液和肺中中性粒细胞、巨噬细胞、树突状细胞、CD4+和CD8+T淋巴细胞的数量，并增加了支气管周围淋巴滤泡的大小和数量。相比之下，在空气暴露或CS暴露的scid小鼠肺中，既无法识别B淋巴细胞，也无法识别T淋巴细胞，也看不到淋巴滤泡。重要的是，慢性CS暴露在野生型动物和scid小鼠中均诱导了肺气肿，CS暴露动物与空气暴露动物相比，平均线性截距和破坏指数显著增加即证明了这一点。与空气暴露的同窝小鼠相比，CS诱导的肺气肿与CS暴露的Balb/c和scid小鼠肺中基质金属蛋白酶-12的mRNA表达增加以及BAL液中肿瘤坏死因子-α的蛋白水平增加有关。
本研究表明，在慢性CS暴露下发生肺气肿本身并不需要适应性免疫系统，因为在缺乏淋巴滤泡以及功能性B细胞和T细胞的scid小鼠中也可诱导肺气肿。
