MESOTHELIAL CELL ACTIVATION IN ASBESTOS INDUCED INJURY

石棉损伤中的间皮细胞激活

• 批准号: 2519484
• 负责人: ELLIOTT KAGAN
• 金额: $ 20.35万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519484
• 关键词: alveolar macrophages; asbestos; cell adhesion molecules; cellular pathology; chemoattractants; confocal scanning microscopy; disease /disorder model; fibronectins; gene expression; interleukin 1; laboratory rat; lung injury; lung lavage; pathology; phagocytosis; platelet derived growth factor; pleural cavity; protein isoforms; pulmonary fibrosis /granuloma; receptor expression; tissue /cell culture; transforming growth factors

Pleural fibrosis is the most common toxicologic manifestation of human asbestos-induced disease. Furthermore, asbestos-related pleural fibrosis has important clinical significance, since it can cause pulmonary restriction and is a marker of increased risk for asbestos-related cancers. However, the mechanisms governing asbestos-mediated pleural fibrosis are poorly understood, and there also has been a long-standing controversy regarding the potential of different commercial types of asbestos to cause pleural injury. In this proposal, it is postulated that inhaled asbestos fibers are phagocytized by pleural mesothelial cells and pleural macrophages, which induces upregulation of certain cytokines, chemotactic proteins and adhesion molecules by these cells. To address this hypothesis, the proposed research will have two components: one will entail the use of an animal inhalational model of asbestos exposure and the other will utilize a number of in vitro studies. The Specific Aims are: (1) to determine, using a rat inhalational model, whether a fiber gradient exists with respect to the phagocytosis of amphibole (crocidolite) versus serpentine (chrysotile) asbestos fibers by pleural mesothelial cells and pleural macrophages, and to determine whether asbestos inhalation enhances pleural macrophage recruitment and activation; (2) to determine whether in vitro exposure of rat pleural mesothelial cells to asbestos fibers induces upregulation of the adhesion proteins, fibronectin and ICAM-I, and the cytokines, interleukin-1, (IL- 1), platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1); (3) to determine whether in vitro exposure of rat pleural macrophages to asbestos fibers induces upregulation of the adhesion protein, LFA-1, the pro- inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and MCP-1, and the fibroblast growth factors, fibronectin, IL-1, TGF-beta and PDGF; (4) to determine whether in vitro asbestos exposure enhances the adherence of rat pleural macrophages to rat pleural mesothelial cells in the context of adhesion molecule expression. For the in vitro studies, comparisons will be made between the effects of chrysotile and crocidolite asbestos and those of non-fibrogenic control particulates, MMVF11 fibers and carbonyl iron particles. For the inhalational toxicology studies, comparisons will be made between the effects of both types of asbestos inhalation and the effects of sham exposure. The proposed studies have important significance for the pathogenesis of asbestos-induced pleural injury.

胸膜纤维化是人类最常见的毒理学表现， 石棉引起的疾病。此外，石棉相关的胸膜纤维化 具有重要的临床意义，因为它可以引起肺 限制，是石棉相关风险增加的标志 癌的然而，石棉介导的胸膜炎的机制 纤维化知之甚少，而且长期以来， 关于不同商业类型的 石棉导致胸膜损伤 在该提案中，假定 吸入的石棉纤维被胸膜间皮细胞吞噬， 胸膜巨噬细胞，其诱导某些细胞因子的上调， 趋化蛋白和粘附分子。解决 根据这一假设，拟议的研究将有两个组成部分：一个将 需要使用石棉暴露的动物吸入模型， 另一个将利用一些体外研究。具体目标 （1）使用大鼠吸入模型，确定纤维是否 角闪石的吞噬作用存在梯度 （青石棉）与蛇纹石（温石棉）石棉纤维的胸膜 间皮细胞和胸膜巨噬细胞，并确定是否 石棉吸入增强胸膜巨噬细胞募集， 激活;（2）确定体外暴露大鼠胸膜是否 间皮细胞对石棉纤维的粘附诱导上调 蛋白质，纤连蛋白和ICAM-1，以及细胞因子，白细胞介素-1（IL-1）， 1）、血小板衍生生长因子（PDGF）、转化生长因子-β （3）TGF-β和单核细胞趋化蛋白-1（MCP-1）; 确定大鼠胸膜巨噬细胞体外暴露于石棉是否 纤维诱导粘附蛋白，LFA-1，前 炎性细胞因子，肿瘤坏死因子-α（TNF-α）和MCP-1， 以及成纤维细胞生长因子、纤连蛋白、IL-1、TGF-β和PDGF; (4)以确定体外石棉暴露是否会增强 大鼠胸膜巨噬细胞转化为大鼠胸膜间皮细胞 粘附分子的表达。对于体外研究，比较 会使温石棉和青石棉之间的影响 以及非纤维化对照颗粒、MMVF 11纤维和 羰基铁颗粒。对于吸入毒理学研究， 将对两种石棉的影响进行比较 吸入和假暴露的影响。拟议的研究有 对石棉胸膜炎发病机制的重要意义 损伤