MESOTHELIAL CELL ACTIVATION IN ASBESTOS INDUCED 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 癌症。然而，石棉介导的胸膜的机制 人们对纤维化知之甚少，也有一个长期存在的 关于不同商业类型的潜力的争议 石棉会造成胸膜损伤。在这项提案中，假设 吸入的石棉纤维被胸膜间皮细胞吞噬，并 胸膜巨噬细胞，可以诱导某些细胞因子的上调， 趋化蛋白和黏附分子通过这些细胞。致信地址 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和 另一项研究将利用一些体外研究。具体目标 是：(1)使用大鼠吸入模型来确定纤维是否 角闪石的吞噬作用存在梯度 (青石棉)与蛇纹石(温石棉)石棉纤维的胸膜对比 间皮细胞和胸膜巨噬细胞，并确定 石棉吸入增强胸膜巨噬细胞募集和 (2)测定大鼠胸膜的体外暴露 间皮细胞对石棉纤维的粘附性上调 蛋白质、纤维连接蛋白和ICAM-I以及细胞因子白介素1(IL-1)。 1)、血小板衍生生长因子(PDGF)、转化生长因子β 转化生长因子-β和单核细胞趋化蛋白-1； 测定石棉对大鼠胸膜巨噬细胞的体外暴露 纤维诱导黏附蛋白LFA-1表达上调，从而促进细胞外基质的形成。 炎性细胞因子、肿瘤坏死因子-α和单核细胞趋化蛋白-1， 成纤维细胞生长因子、纤维连接蛋白、IL-1、转化生长因子-β和血小板衍生生长因子； (4)确定体外接触石棉是否会增强粘附性 大鼠胸膜巨噬细胞对大鼠胸膜间皮细胞的影响 黏附分子的表达。对于体外研究，比较 会产生温石棉和青石棉之间的影响 以及非致纤维化对照颗粒、MMVF11纤维和 羰基铁颗粒。用于吸入毒理学研究， 将对这两种石棉的影响进行比较 吸入和假暴露的影响。拟议的研究包括 石棉致胸膜病变发病机制的重要意义 受伤。

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.