Lee K Monica, Renne Roger A, Harbo Sam J, Clark Mark L, Johnson Renee E, Gideon Kathy M
Battelle Toxicology Northwest, Richland, Washington, USA.
Inhal Toxicol. 2007 Jan;19(1):23-35. doi: 10.1080/08958370600985784.
AKR/J mice were exposed to cigarette smoke (CS) and/or lipopolysaccharide (LPS) via inhalation for 3 wk and pulmonary responses were evaluated. The objective was to explore the feasibility of coexposing LPS with cigarette smoke under a subacute exposure, as a surrogate for viral or bacterial insults, that would mimic the pathogenesis of infection-related chronic obstructive pulmonary disease (COPD) exacerbations. The study was the first step in an effort to develop a rodent COPD model in which morphologic lesions of COPD develop in a shorter period of exposure and more closely simulate human COPD. Mice were exposed 6 h/day, 5 days/wk for 3 wk to one of the following: (1) sham control: filtered air; (2) CS: 250 microg/L wet total particulate matter (WTPM) for 5 h/day followed by 1 h/day air; (3) LPS: 0.5 microg/L LPS (055:B5 Escherichia coli; 3,000,000 EU/mg) for the last 1 h/day 2 day/wk (following 5 h/day of filtered air); and (4) CS/LPS: CS 5 h/day followed by air or LPS (2 days/wk) for 1 h/day. After the last exposure, animals were necropsied and subjected to bronchoalveolar lavage (BAL) or histopathology. The BAL neutrophil counts were highest in the LPS group, while macrophage counts were higher in the CS/LPS group than other exposed groups. The LPS group displayed the greatest increases in BAL cytokines, while KC (keratinocyte-derived chemokine) and TARC (thymus and activation-regulated chemokine) were highest in the CS group. The CS/LPS group had generally lower cytokine levels relative to the LPS or CS groups, except for the levels of RANTES and G-CSF (granulocyte-colony stimulating factor) comparable to the LPS group. At microscopic examination of lung sections, cellular inflammatory infiltrates were most notable in the CS/LPS group, which had a diffuse, predominantly macrophage infiltrate with fewer neutrophils. The LPS group had predominantly neutrophils in the pulmonary infiltrate and the CS group had a predominantly macrophage infiltrate in alveolar ducts and adjacent alveoli. Apoptotic labeling of lung cells was highest with the CS/LPS group. In summary, the CS/LPS group displayed greater cellular infiltration and apoptotic responses in the lung with an indication of immunosuppressive effects (lower BAL cytokines) than the CS or LPS group, suggesting that the CS/LPS model shows promise to be further explored as an animal model for studying pathogenesis of COPD exacerbations. A longer term study with interim assessments is needed to confirm that the subacute responses observed in the CS/LPS group will result in greater severity of COPD-related pulmonary lesions following prolonged exposures.
将AKR/J小鼠通过吸入方式暴露于香烟烟雾（CS）和/或脂多糖（LPS）中3周，并评估肺部反应。目的是探讨在亚急性暴露条件下将LPS与香烟烟雾共同暴露的可行性，以此作为病毒或细菌感染的替代物，模拟感染相关慢性阻塞性肺疾病（COPD）急性加重的发病机制。该研究是开发啮齿类COPD模型的第一步，在该模型中，COPD的形态学病变可在更短的暴露时间内形成，且更接近地模拟人类COPD。小鼠每天暴露6小时，每周5天，持续3周，暴露于以下其中一种环境：（1）假手术对照组：过滤空气；（2）CS组：每天5小时暴露于250微克/升的湿总颗粒物（WTPM）中，随后1小时暴露于空气中；（3）LPS组：每周2天，在每天最后1小时暴露于0.5微克/升的LPS（055:B5大肠杆菌；3,000,000 EU/毫克）（在每天5小时过滤空气之后）；（4）CS/LPS组：每天5小时暴露于CS中，随后1小时暴露于空气或LPS（每周2天）。在最后一次暴露后，对动物进行尸检并进行支气管肺泡灌洗（BAL）或组织病理学检查。BAL中性粒细胞计数在LPS组中最高，而巨噬细胞计数在CS/LPS组中高于其他暴露组。LPS组BAL细胞因子增加最为显著，而角质形成细胞衍生趋化因子（KC）和胸腺与活化调节趋化因子（TARC）在CS组中最高。CS/LPS组的细胞因子水平相对于LPS或CS组总体较低，除了调节激活正常T细胞表达和分泌的趋化因子（RANTES）和粒细胞集落刺激因子（G-CSF）水平与LPS组相当。在肺切片显微镜检查中，细胞炎性浸润在CS/LPS组中最为明显，该组有弥漫性、主要为巨噬细胞浸润，中性粒细胞较少。LPS组肺部浸润主要为中性粒细胞，CS组在肺泡导管和相邻肺泡中主要为巨噬细胞浸润。肺细胞的凋亡标记在CS/LPS组中最高。总之，与CS或LPS组相比，CS/LPS组在肺部表现出更大的细胞浸润和凋亡反应，并显示出免疫抑制作用（较低的BAL细胞因子），这表明CS/LPS模型有望作为研究COPD急性加重发病机制的动物模型进一步探索。需要进行一项长期研究并进行中期评估，以确认在CS/LPS组中观察到的亚急性反应在长期暴露后是否会导致更严重的COPD相关肺部病变。
