Chemical & Biomolecular Engineering, Georgia Institute of Technology, United States.
CEMB/DART/NIOSH/CDC, United States.
Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):58-67. doi: 10.1016/j.bbagen.2016.09.031. Epub 2016 Oct 23.
In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models.
Murine alveolar macrophages were exposed to short and long populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1α, COX-2, PGE) were measured.
Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production.
Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data.
The single physical parameter of length can be used to directly assess the contributions of length against other physicochemical fiber properties to disease endpoints.
在肺部，巨噬细胞试图吞噬吸入的高纵横比的致病物质，在此过程中分泌炎症分子。巨噬细胞无法清除这些物质会导致慢性炎症和疾病。纤维长度如何影响这些效应的生物物理和生化机制仍未确定。本研究评估了纤维长度对吞噬作用和非细胞毒性纤维的分子炎症反应的作用，从而能够开发定量基于长度的模型。
用通过连续沉降和重复粉碎分别产生的短纤维和长纤维 JM-100 玻璃纤维，暴露于肺泡巨噬细胞。使用延时视频显微镜观察纤维与巨噬细胞之间的相互作用，并通过流式细胞术进行定量。测量炎症生物分子（TNF-α、IL-1α、COX-2、PGE）。
短纤维的摄取比长纤维更容易，但长纤维更能刺激炎症分子。刺激导致炎症生物分子呈剂量依赖性分泌，但无细胞毒性或强 ROS 产生。使用基于长度的效力模型，用测量的纤维长度分布评估线性细胞因子剂量反应曲线，确定了导致吞噬作用受阻和炎症生物分子产生增加的临界纤维长度。
与长纤维相比，短纤维在炎症反应中作用较小。通过将剂量反应曲线拟合到纤维分布数据，可以定量确定发生吞噬作用受阻的临界长度。
长度这一单一物理参数可用于直接评估长度相对于其他纤维理化性质对疾病终点的贡献。
