Stressing fibrogenesis in cell culture.
Stressing fibrogenesis in cell culture.
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强调细胞培养中的纤维发生。
DOI：
10.1165/ajrcmb.21.4.f161
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Brody,AR
中科院分区：
文献类型：
--
作者：
Morris,GF;Brody,AR
吸入的纤维颗粒沉积在肺外周引起慢性炎症反应，导致产生纤维化介质（1，2）。石棉肺或硅肺中观察到的纤维化，尽管组织病理学表现不同，但导致肺结构类似的破坏，细胞外基质沉积和间质性肺纤维化（IPF）的细胞增殖特征（1）。吸入颗粒物诱导纤维化的机制尚未完全了解，但似乎涉及颗粒物的物理和化学性质。颗粒的肺部滞留与长度相关，而表面通过吸附和催化特性促进生物活性（1）。为了理解IPF的复杂性，已经开发了纤维诱导的肺部疾病的实验动物模型作为人类疾病的范例。纤维诱导的肺部疾病在动物模型中的发展模式与在人类中观察到的模式相似（3）。因此，我们对肺部对吸入颗粒的初始反应的理解主要来自于短时间内暴露于高浓度颗粒的动物（4）。在啮齿动物模型中的观察结果表明，颗粒诱导的肺上皮损伤引发了一系列导致纤维化的事件（1，2，4）。活性氧（ROS）由活化的炎症细胞产生，通过颗粒表面的催化作用和颗粒-细胞相互作用，可能是上皮损伤的原因（1，2）。受损的上皮细胞释放细胞因子，启动巨噬细胞积聚并开始伤口愈合过程。积聚的肺泡巨噬细胞还分泌炎症和纤维化介质，肺泡II型细胞增殖以再生受损的上皮（1，2，5）。间充质细胞的同时增殖和细胞外基质的沉积导致纤维化瘢痕的发展。动物模型中纤维化过程的复杂性和肺细胞的异质性阻碍了对任何特定介质的特定作用的识别，并且这些因素之间的相互作用进一步混淆了问题。为了减少纤维化分析的复杂性，在细胞培养中概括了尘肺动物模型中的一些事件。早在20世纪60年代，细胞培养实验就表明巨噬细胞在硅肺中起着核心作用。二氧化硅对培养物中的巨噬细胞具有毒性，暴露于二氧化硅的巨噬细胞的提取物刺激成纤维细胞的胶原蛋白积累（6）。这些早期发现提示了颗粒诱导的纤维形成模型，其中由颗粒吞噬作用引起的巨噬细胞死亡释放破坏性细胞内酶，并且释放的颗粒的再摄取使该过程持续，导致慢性组织损伤。多年后，来自间质性肺病患者的肺泡巨噬细胞显示表达升高水平的转化生长因子-β（TGF-β）（7），其是细胞外基质沉积的有效诱导剂（8）。还发现肺纤维化患者的肺泡巨噬细胞分泌肺成纤维细胞的生长因子（9），随后的细胞培养实验证明颗粒暴露的巨噬细胞释放血小板源性生长因子（10）。这些和许多最近的研究结果表明，目前公认的模型，其中颗粒活化的巨噬细胞和上皮细胞招募成纤维细胞的损伤部位，刺激其增殖，并促进细胞外基质的合成。
Inhaled fibrous particles deposited in the lung periphery elicit a chronic inflammatory response that leads to production of fibrogenic mediators (1, 2). The fibrogenesis observed in asbestosis or silicosis, despite differences in histopathologic appearance, leads to similar disruptions in lung architecture, with deposition of extracellular matrix and cell proliferation characteristic of interstitial pulmonary fibrosis (IPF)(1). The mechanisms of fibrogenesis induced by inhaled particles are not completely understood but appear to involve both physical and chemical properties of the particles. Pulmonary retention of particles correlates with length, whereas the surfaces promote bioreactivity through adsorptive and catalytic properties (1). To understand the complexities of IPF, experimental animal models of fiber-induced lung diseases have been developed to serve as a paradigm for human diseases. Fiber-induced lung diseases develop in animal models in patterns similar to those observed in humans (3). Consequently, our understanding of the initial response of the lung to inhaled particles comes primarily from animals exposed to particles at high concentrations for short time periods (4). Observations in rodent models indicate that particle-induced injury of the pulmonary epithelium initiates a cascade of events leading to fibrogenesis (1, 2, 4). Reactive oxygen species (ROS) generated by activated inflammatory cells, by catalysis on the particle surface and by particle-cell interactions, are probably contributors to injury of the epithelium (1, 2). The injured epithelium releases cytokines that initiate macrophage accumulation and begin the process of wound healing. The accumulated alveolar macrophages also secrete inflammatory and fibrogenic mediators, and alveolar type II cells proliferate to regenerate the disrupted epithelium (1, 2, 5). Concurrent proliferation of mesenchymal cells and deposition of extracellular matrix lead to development of the fibrotic scar. The complexity of the fibrogenic process in animal models and cellular heterogeneity of the lung hinder identification of a specific role for any particular mediator, and interactions among these factors further confound the problem. To reduce the complexity of the analyses of fibrogenesis, some of the events in animal models of pneumoconiosis have been recapitulated in cell culture. As early as the 1960s, cell culture experiments suggested a central role for macrophages in silicosis. Silica was toxic to macrophages in culture, and an extract from silica-exposed macrophages stimulated collagen accumulation by fibroblasts (6). These early findings prompted a model of particle-induced fibrogenesis, in which macrophage death caused by particle phagocytosis released destructive intracellular enzymes, and reuptake of released particles perpetuated the process leading to chronic tissue injury. Many years later, alveolar macrophages from patients with interstitial lung disorders were shown to express elevated levels of transforming growth factor-ß (TGF-ß)(7), a potent inducer of extracellular matrix deposition (8). Alveolar macrophages from patients with lung fibrosis were also found to secrete growth factors for lung fibroblasts (9), and subsequent cell culture experiments demonstrated release of platelet-derived growth factor by particle-exposed macrophages (10). These and many more recent findings suggest the currently accepted model wherein particle-activated macrophages and epithelial cells recruit fibroblasts to the sites of injury, stimulate their proliferation, and promote synthesis of extracellular matrix.Much of the analyses of the response of fibers in cell culture have focused on alveolar macrophages …