Veterans Affairs Nebraska-Western Iowa Health Care System, Research Service, Omaha, NE, USA; Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Int Immunopharmacol. 2021 Nov;100:108069. doi: 10.1016/j.intimp.2021.108069. Epub 2021 Aug 27.
Airborne biohazards are risk factors in the development and severity of rheumatoid arthritis (RA) and RA-associated lung disease, yet the mechanisms explaining this relationship remain unclear. Lipopolysaccharide (LPS, endotoxin) is a ubiquitous inflammatory agent in numerous environmental and occupational air pollutant settings recognized to induce airway inflammation. Combining repetitive LPS inhalation exposures with the collagen induced arthritis (CIA) model, DBA1/J mice were assigned to either: sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS 100 ng inhalation), or CIA + LPS for 5 weeks. Serum anti-citrullinated (CIT) protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) antibodies were strikingly potentiated with co-exposure (CIA + LPS). CIT- and MAA-modified lung proteins were increased with co-exposure and co-localized across treatment groups. Inhaled LPS exacerbated arthritis with CIA + LPS > LPS > CIA versus sham. Periarticular bone loss was demonstrated in CIA and CIA + LPS but not in LPS alone. LPS induced airway inflammation and neutrophil infiltrates were reduced with co-exposure (CIA + LPS). Potentially signaling transition to pro-fibrotic processes, there were increased infiltrates of activated CD11cCD11b macrophages and transitioning CD11cCD11b monocyte-macrophage populations with CIA + LPS. Moreover, several lung remodeling proteins including fibronectin and matrix metalloproteinases as well as complement C5a were potentiated with CIA + LPS compared to other treatment groups. IL-33 concentrations in lung homogenates were enhanced with CIA + LPS with IL-33 lung staining driven by LPS. IL-33 expression was also significantly increased in lung tissues from patients with RA-associated lung disease (N = 8) versus controls (N = 7). These findings suggest that patients with RA may be more susceptible to developing interstitial lung disease following airborne biohazard exposures enriched in LPS.
空气中的生物危害是类风湿关节炎（RA）和与 RA 相关的肺部疾病发展和严重程度的危险因素，但解释这种关系的机制仍不清楚。脂多糖（LPS，内毒素）是许多环境和职业空气污染物环境中普遍存在的炎症介质，已知其可诱导气道炎症。将重复的 LPS 吸入暴露与胶原诱导性关节炎（CIA）模型相结合，将 DBA1/J 小鼠分为以下几组：假手术（生理盐水注射/生理盐水吸入）、CIA（CIA/生理盐水）、LPS（生理盐水/LPS100ng 吸入）或 CIA+LPS 共暴露 5 周。血清抗瓜氨酸（CIT）蛋白抗体（ACPA）和抗丙二醛-乙醛（MAA）抗体在共暴露时明显增强（CIA+LPS）。共暴露时 CIT 和 MAA 修饰的肺蛋白增加，并在各组中共同定位。LPS 共暴露（CIA+LPS）加剧了关节炎，其严重程度大于 LPS 组和 CIA 组。在 CIA 和 CIA+LPS 中，但不在 LPS 组中，发现了关节周围骨丢失。LPS 诱导的气道炎症和中性粒细胞浸润在共暴露时减少（CIA+LPS）。潜在地提示向促纤维化过程的转变，有更多的活化的 CD11cCD11b 巨噬细胞和过渡的 CD11cCD11b 单核-巨噬细胞群浸润，与 CIA+LPS 相关。此外，与其他治疗组相比，几种肺重塑蛋白，包括纤连蛋白和基质金属蛋白酶以及补体 C5a，在 CIA+LPS 中增强。LPS 刺激的 CIA+LPS 组肺匀浆中 IL-33 浓度升高，IL-33 肺染色由 LPS 驱动。在患有与 RA 相关的肺部疾病的患者（N=8）与对照组（N=7）的肺组织中，IL-33 的表达也显著增加。这些发现表明，RA 患者在空气中的生物危害暴露中富含 LPS 后，可能更容易发生间质性肺病。
