Hill David B, Vasquez Paula A, Mellnik John, McKinley Scott A, Vose Aaron, Mu Frank, Henderson Ashley G, Donaldson Scott H, Alexis Neil E, Boucher Richard C, Forest M Gregory
Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Physics and Astronomy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Departments of Mathematics and Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
PLoS One. 2014 Feb 18;9(2):e87681. doi: 10.1371/journal.pone.0087681. eCollection 2014.
In human airways diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), host defense is compromised and airways inflammation and infection often result. Mucus clearance and trapping of inhaled pathogens constitute key elements of host defense. Clearance rates are governed by mucus viscous and elastic moduli at physiological driving frequencies, whereas transport of trapped pathogens in mucus layers is governed by diffusivity. There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties. We tested the hypothesis that mucus solids concentration, indexed as weight percent solids (wt%), is such a biomarker. Passive microbead rheology was employed to determine both diffusive and viscoelastic properties of mucus harvested from human bronchial epithelial (HBE) cultures. Guided by sputum from healthy (1.5-2.5 wt%) and diseased (COPD, CF; 5 wt%) subjects, mucus samples were generated in vitro to mimic in vivo physiology, including intermediate range wt% to represent disease progression. Analyses of microbead datasets showed mucus diffusive properties and viscoelastic moduli scale robustly with wt%. Importantly, prominent changes in both biophysical properties arose at ∼4 wt%, consistent with a gel transition (from a more viscous-dominated solution to a more elastic-dominated gel). These findings have significant implications for: (1) penetration of cilia into the mucus layer and effectiveness of mucus transport; and (2) diffusion vs. immobilization of micro-scale particles relevant to mucus barrier properties. These data provide compelling evidence for mucus solids concentration as a baseline clinical biomarker of mucus barrier and clearance functions.
在包括囊性纤维化（CF）和慢性阻塞性肺疾病（COPD）在内的人类气道疾病中，宿主防御功能受损，常导致气道炎症和感染。黏液清除以及捕获吸入的病原体是宿主防御的关键要素。清除率由生理驱动频率下黏液的黏性和弹性模量决定，而被困病原体在黏液层中的运输则由扩散率决定。显然需要与这些特性相关的简单有效的气道疾病临床生物标志物。我们检验了这样一种假设，即黏液固体浓度（以固体重量百分比（wt%）表示）就是这样一种生物标志物。采用被动微珠流变学来测定从人支气管上皮（HBE）培养物中获取的黏液的扩散和黏弹性特性。以健康受试者（1.5 - 2.5 wt%）和患病受试者（COPD、CF；5 wt%）的痰液为指导，在体外生成黏液样本以模拟体内生理状态，包括代表疾病进展的中等范围的wt%。对微珠数据集的分析表明，黏液的扩散特性和黏弹性模量与wt%密切相关。重要的是，两种生物物理特性在约4 wt%时都出现了显著变化，这与凝胶转变（从以黏性为主的溶液转变为以弹性为主的凝胶）一致。这些发现对以下方面具有重要意义：（1）纤毛穿透黏液层的程度以及黏液运输的有效性；（2）与黏液屏障特性相关的微观颗粒的扩散与固定。这些数据为黏液固体浓度作为黏液屏障和清除功能的基线临床生物标志物提供了有力证据。
