Dong Jie, Porter Dale W, Batteli Lori A, Wolfarth Michael G, Richardson Diana L, Ma Qiang
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Road, Mailstop 3014, Morgantown, WV, 26505, USA.
Arch Toxicol. 2015 Apr;89(4):621-33. doi: 10.1007/s00204-014-1428-y. Epub 2014 Dec 16.
Multi-walled carbon nanotubes (MWCNT) are new materials with a wide range of industrial and commercial applications. However, their nano-scaled size and fiber-like shape render them respirable and potentially fibrogenic if inhaled into the lungs. To understand MWCNT fibrogenesis, we analyzed the pathologic and molecular aspects of the early phase response to MWCNT in mouse lungs. MWCNT induced rapid and pronounced lesions in the lungs characterized by increased cellularity and formation of fibrotic foci, most notably near where MWCNT deposited, within 14 days post-exposure. Deposition of collagen fibers was markedly increased in the alveolar septa and fibrotic foci, accompanied by elevated expression of fibrotic genes Col1a1, Col1a2, and Fn1 at both mRNA and protein levels. Fibrosis was induced rapidly at 40 μg, wherein fibrotic changes were detected on day 1 and reached a maximal intensity on day 7 through day 14. Induction of fibrosis was dose-dependent at the dose range of 5-40 μg, 7 days post-exposure. MWCNT elicited rapid and prominent infiltrations of neutrophils and macrophages alongside fibrosis implicating acute inflammation in the fibrotic response. At the molecular level, MWCNT induced elevated expression of proinflammatory cytokines TNFα, IL1α, IL1β, IL6, and CCL2 in lung tissues as well as the bronchoalveolar lavage fluid, in a dose- and time-dependent manner. MWCNT also increased the expression of fibrogenic growth factors TGF-β1 and PDGF-A in the lungs significantly. These findings underscore the interplay between acute inflammation and the early fibrotic response in the initiation and propagation of pulmonary fibrosis induced by MWCNT.
多壁碳纳米管（MWCNT）是具有广泛工业和商业应用的新型材料。然而，它们的纳米级尺寸和纤维状形状使其可被吸入肺部，并且如果被吸入肺部可能具有致纤维化性。为了了解MWCNT的纤维化发生机制，我们分析了小鼠肺部对MWCNT早期反应的病理和分子方面。MWCNT在暴露后14天内可在肺部诱导快速且明显的病变，其特征为细胞增多和纤维化灶形成，最明显的是在MWCNT沉积的部位附近。肺泡间隔和纤维化灶中胶原纤维的沉积明显增加，同时纤维化基因Col1a1、Col1a2和Fn1在mRNA和蛋白质水平上的表达均升高。在40μg时迅速诱导纤维化，其中在第1天检测到纤维化变化，并在第7天至第14天达到最大强度。在暴露后7天，在5-40μg的剂量范围内，纤维化的诱导呈剂量依赖性。MWCNT在纤维化的同时引发了中性粒细胞和巨噬细胞的快速且显著浸润，这表明急性炎症参与了纤维化反应。在分子水平上，MWCNT以剂量和时间依赖性方式诱导肺组织以及支气管肺泡灌洗液中促炎细胞因子TNFα、IL1α、IL1β、IL6和CCL2的表达升高。MWCNT还显著增加了肺中成纤维生长因子TGF-β1和PDGF-A的表达。这些发现强调了急性炎症与早期纤维化反应在MWCNT诱导的肺纤维化起始和传播中的相互作用。
