Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Veterans Affairs Nebraska-Western Iowa Health Care System, Research Service, Omaha, NE, USA.
J Bone Miner Res. 2019 Sep;34(9):1733-1743. doi: 10.1002/jbmr.3745. Epub 2019 Jun 24.
Rheumatoid arthritis (RA) is characterized by extra-articular involvement including lung disease, yet the mechanisms linking the two conditions are poorly understood. The collagen-induced arthritis (CIA) model was combined with the organic dust extract (ODE) airway inflammatory model to assess bone/joint-lung inflammatory outcomes. DBA/1J mice were intranasally treated with saline or ODE daily for 5 weeks. CIA was induced on days 1 and 21. Treatment groups included sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE), and CIA + ODE (CIA/ODE). Arthritis inflammatory scores, bones, bronchoalveolar lavage fluid, lung tissues, and serum were assessed. In DBA/1J male mice, arthritis was increased in CIA + ODE > CIA > ODE versus sham. Micro-computed tomography (µCT) demonstrated that loss of BMD and volume and deterioration of bone microarchitecture was greatest in CIA + ODE. However, ODE-induced airway neutrophil influx and inflammatory cytokine/chemokine levels in lavage fluids were increased in ODE > CIA + ODE versus sham. Activated lung CD11c CD11b macrophages were increased in ODE > CIA + ODE > CIA pattern, whereas lung hyaluronan, fibronectin, and amphiregulin levels were greatest in CIA + ODE. Serum autoantibody and inflammatory marker concentrations varied among experimental groups. Compared with male mice, female mice showed less articular and pulmonary disease. The interaction of inhalation-induced airway inflammation and arthritis induction resulted in compartmentalized responses with the greatest degree of arthritis and bone loss in male mice with combined exposures. Data also support suppression of the lung inflammatory response, but increases in extracellular matrix protein deposition/interstitial disease in the setting of arthritis. This coexposure model could be exploited to better understand and treat RA-lung disease. © 2019 American Society for Bone and Mineral Research.
类风湿关节炎（RA）的特征是关节外受累，包括肺部疾病，但将这两种情况联系起来的机制还知之甚少。本研究将胶原诱导性关节炎（CIA）模型与有机尘埃提取物（ODE）气道炎症模型相结合，以评估骨/关节-肺炎症结果。将 DBA/1J 小鼠每日用生理盐水或 ODE 经鼻处理 5 周。在第 1 天和第 21 天诱导 CIA。治疗组包括假手术（生理盐水注射/生理盐水吸入）、CIA（CIA/生理盐水）、ODE（生理盐水/ODE）和 CIA+ODE（CIA/ODE）。评估关节炎炎症评分、骨骼、支气管肺泡灌洗液、肺组织和血清。在 DBA/1J 雄性小鼠中，与 sham 相比，CIA+ODE＞CIA＞ODE 导致关节炎加重。微计算机断层扫描（µCT）显示 CIA+ODE 导致 BMD 和体积丢失以及骨微结构恶化最严重。然而，与 sham 相比，ODE 诱导的气道中性粒细胞浸润和灌洗液中炎症细胞因子/趋化因子水平在 ODE＞CIA+ODE 中增加。在 ODE＞CIA+ODE＞CIA 模式中，激活的肺 CD11c CD11b 巨噬细胞增加，而在 CIA+ODE 中肺透明质酸、纤维连接蛋白和 Amphiregulin 水平最高。与实验性关节炎和骨丢失有关的各种组织细胞因子和趋化因子也与关节炎和骨丢失的严重程度呈正相关。与雄性小鼠相比，雌性小鼠的关节和肺部疾病较少。与关节炎诱导同时吸入诱导的气道炎症导致隔室化反应，在合并暴露的雄性小鼠中关节炎和骨丢失最严重。数据还支持抑制肺部炎症反应，但在关节炎的情况下增加细胞外基质蛋白沉积/间质疾病。这种共暴露模型可用于更好地理解和治疗 RA-肺部疾病。
