Abstract：
Idiopathic pulmonary fibrosis (IPF) is an aggressive and thus far incurable disease, characterized by aberrant fibroblast-mediated extracellular matrix deposition. Our understanding of the disease etiology is incomplete; however, there is consensus that a reduction-oxidation (redox) imbalance plays a role. In this study we use the autofluorescent properties of two redox molecules, NAD(P)H and FAD, to quantify changes in their relative abundance in living lung tissue of mice with experimental lung fibrosis, and in freshly isolated cells from mouse lungs and humans with IPF. Our results identify cell population-specific intracellular redox changes in the lungs in experimental and human fibrosis. We focus particularly on redox changes within collagen producing cells, where we identified a bimodal distribution of NAD(P)H concentrations, establishing NAD(P)Hhigh and NAD(P)Hlow sub-populations. NAD(P)Hhigh fibroblasts exhibited elevated pro-fibrotic gene expression and decreased collagenolytic protease activity relative to NAD(P)Hlow fibroblasts. The NAD(P)Hhigh population was present in healthy lungs but expanded with time after bleomycin injury suggesting a potential role in fibrosis progression. We identified a similar increased abundance of NAD(P)Hhigh cells in freshly dissociated lungs of subjects with IPF relative to controls, and similar reductions in collagenolytic activity in this cell population. These data highlight the complexity of redox state changes in experimental and human pulmonary fibrosis and the need for selective approaches to restore redox imbalances in the fibrotic lung.
摘要：
特发性肺纤维化（IPF）是一种侵袭性的，迄今为止无法治愈的疾病，以异常成纤维细胞介导的细胞外基质沉积为特征。我们对这种疾病病因的理解是不完整的；然而，有一个共识，还原-氧化（氧化还原）失衡发挥作用。在这项研究中，我们使用两个氧化还原分子的自发荧光性质，NAD(P)H和FAD,为了量化它们在实验性肺纤维化小鼠的活肺组织中的相对丰度变化，以及来自患有IPF的小鼠肺和人类的新鲜分离细胞。我们的结果确定了实验性和人类纤维化中肺部细胞群特异性细胞内氧化还原变化。我们特别关注胶原蛋白产生细胞内的氧化还原变化，我们确定了NAD（P）H浓度的双峰分布，建立NAD(P)High和NAD(P)Hlow亚群。NAD(P)Hhigh成纤维细胞相对于NAD(P)Hlow成纤维细胞表现出升高的促纤维化基因表达和降低的胶原分解蛋白酶活性。NAD（P）Hhigh人群存在于健康的肺中，但在博来霉素损伤后随着时间的推移而扩大，表明在纤维化进展中具有潜在作用。我们发现，与对照组相比，IPF患者新鲜分离的肺中NAD（P）Hhigh细胞的丰度相似。以及该细胞群中胶原酶活性的类似降低。这些数据突出了实验性和人类肺纤维化中氧化还原状态变化的复杂性，以及对恢复纤维化肺中氧化还原失衡的选择性方法的需求。
