Department of Medicine, National Jewish Health, 1400 Jackson Street, Molly Blank Building, J203, Denver, CO, 80206, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Respir Res. 2018 May 31;19(1):107. doi: 10.1186/s12931-018-0812-1.
Several inflammatory lung diseases display abundant presence of hyaluronic acid (HA) bound to heavy chains (HC) of serum protein inter-alpha-inhibitor (IαI) in the extracellular matrix. The HC-HA modification is critical to neutrophil sequestration in liver sinusoids and to survival during experimental lipopolysaccharide (LPS)-induced sepsis. Therefore, the covalent HC-HA binding, which is exclusively mediated by tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6), may play an important role in the onset or the resolution of lung inflammation in acute lung injury (ALI) induced by respiratory infection.
Reversible ALI was induced by a single intratracheal instillation of LPS or Pseudomonas aeruginosa in mice and outcomes were studied for up to six days. We measured in the lung or the bronchoalveolar fluid HC-HA formation, HA immunostaining localization and roughness, HA fragment abundance, and markers of lung inflammation and lung injury. We also assessed TSG-6 secretion by TNFα- or LPS-stimulated human alveolar macrophages, lung fibroblast Wi38, and bronchial epithelial BEAS-2B cells.
Extensive HC-modification of lung HA, localized predominantly in the peri-broncho-vascular extracellular matrix, was notable early during the onset of inflammation and was markedly decreased during its resolution. Whereas human alveolar macrophages secreted functional TSG-6 following both TNFα and LPS stimulation, fibroblasts and bronchial epithelial cells responded to only TNFα. Compared to wild type, TSG-6-KO mice, which lacked HC-modified HA, exhibited modest increases in inflammatory cells in the lung, but no significant differences in markers of lung inflammation or injury, including histopathological lung injury scores.
Respiratory infection induces rapid HC modification of HA followed by fragmentation and clearance, with kinetics that parallel the onset and resolution phase of ALI, respectively. Alveolar macrophages may be an important source of pulmonary TSG-6 required for HA remodeling. The formation of HC-modified HA had a minor role in the onset, severity, or resolution of experimental reversible ALI induced by respiratory infection with gram-negative bacteria.
几种炎症性肺病在细胞外基质中显示出大量与血清蛋白 inter-alpha-inhibitor (IαI) 重链 (HC) 结合的透明质酸 (HA)。HC-HA 修饰对于中性粒细胞在肝窦中的隔离以及实验性脂多糖 (LPS) 诱导的败血症中的存活至关重要。因此，这种由肿瘤坏死因子 α (TNFα)-刺激基因-6 (TSG-6) 介导的共价 HC-HA 结合可能在由呼吸道感染引起的急性肺损伤 (ALI) 中发挥重要作用。
通过单次气管内滴注 LPS 或铜绿假单胞菌诱导可逆性 ALI，并在长达 6 天的时间内研究结果。我们测量了肺或支气管肺泡液中 HC-HA 形成、HA 免疫染色定位和粗糙度、HA 片段丰度以及肺炎症和肺损伤标志物。我们还评估了 TNFα 或 LPS 刺激的人肺泡巨噬细胞、肺成纤维细胞 Wi38 和支气管上皮细胞 BEAS-2B 分泌 TSG-6 的情况。
在炎症开始时，肺 HA 的广泛 HC 修饰主要定位于支气管血管周围细胞外基质中，并且在其消退过程中明显减少。尽管人肺泡巨噬细胞在 TNFα 和 LPS 刺激后均可分泌功能性 TSG-6，但成纤维细胞和支气管上皮细胞仅对 TNFα 有反应。与野生型相比，缺乏 HC 修饰 HA 的 TSG-6-KO 小鼠肺部炎症细胞略有增加，但肺炎症或损伤标志物，包括组织病理学肺损伤评分，无显著差异。
呼吸道感染会迅速诱导 HA 的 HC 修饰，随后发生片段化和清除，其动力学分别与 ALI 的发作和消退阶段相平行。肺泡巨噬细胞可能是 HA 重塑所需的肺 TSG-6 的重要来源。HC 修饰 HA 的形成在由革兰氏阴性菌引起的实验性可逆性 ALI 的发作、严重程度或消退中仅发挥次要作用。
