MECHANISMS OF PARTICLE-INDUCED LUNG DISEASE

工作总结：当吸入各种人造颗粒物时，它们是纤维增生性肺部疾病的来源。这些疾病的一个主要特征是肺内结缔组织细胞过度增殖。我们推测，血小板衍生生长因子(PDGF)受体系统在这些疾病的进展中起着关键作用。纤维化颗粒导致肺损伤，刺激巨噬细胞产生炎症介质，如白介素1β(IL-1β)、转化生长因子β1(TGF-β1)和前列腺素E2(PGE2)，调节PDGF受体的表达。我们已经证明，IL-1β上调PDGFα受体，并增加肺成纤维细胞对PDGF的有丝分裂和趋化反应。相反，转化生长因子-β1和前列腺素E_2下调PDGF受体系统，抑制成纤维细胞生长。介导炎症反应和随后的PDGF受体改变的颗粒相关物质是内毒素和金属，如钒。在钒诱导的大鼠肺损伤后，体内发生了PDGFα受体的诱导，并先于成纤维细胞的增殖。IL-1β在体外诱导的PDGFα受体的表达依赖于p38 MAP激酶，而不依赖于细胞外信号调节蛋白(ERKs)或c-jun氨基末端蛋白(JNKs)。我们最近的研究表明，IL-1β不是通过经典的NFkB途径来诱导PDGF受体的表达。未来的工作将集中在：1)阐明介导血小板衍生生长因子受体上调的转录因子(S)；2)过表达可溶性细胞外血小板衍生生长因子受体以抑制大鼠和小鼠肺纤维化的进展。预计这项研究将为肺纤维增生性肺疾病的干预提供策略。-纤维化、肺、巨噬细胞、成纤维细胞、细胞因子、内毒素、石棉、金属

Summary of Work: A variety of man-made particles, when inhaled, are sources of fibroproliferative lung diseases. A key feature of these diseases is the excessive proliferation of connective tissues cells within the lung. We postulate that the platelet-derived growth factor (PDGF) receptor system is pivotal to the progression of these diseases. Fibrogenic particles cause lung injury and stimulate macrophages to produce inflammatory mediators such as interleukin-1beta (IL-1beta), transforming growth factor beta-1 (TGF-beta-1) and prostaglandin-E2 (PGE2) that modulate PDGF receptor expression. We have shown that IL- 1beta upregulates the PDGF alpha receptor and increases the mitogenic and chemotactic responses of lung fibroblasts to PDGF. In contrast, TGF-beta1 and PGE2 down-regulate the PDGF receptor system and suppress fibroblast growth. The particle-associated agents that mediate the inflammatory responses and subsequent PDGF receptor alteration are endotoxin and metals such as vanadium. Induction of PDGF alpha receptor occurs in vivo following vanadium induced lung injury in rats and precedes fibroblast hyperplasia. IL-1beta-induced expression of the PDGF alpha receptor in vitro is dependent on p38 MAP kinase, but not the extracellular-signal regulated kinases (ERKs) or c-Jun N-terminal kinases (JNKs).Our most recent studies, which have investigated nuclear localization of NFkB (p50/p65 proteins) by gel shift/supershift and the coordinated degradation of IkB-alpha, suggest that IL-1beta does not appear to induce the PDGF receptor through a classic NFkB pathway. Future work will focus on: 1) elucidation of transcription factor(s) which mediate PDGF receptor up-regulation and 2) overexpression of a soluble extracellular PDGF receptor to inhibit the progression of lung fibrosis in rats and mice. It is anticipated that this research will lead to strategies for the intervention pulmonary fibroproliferative lung disease. - fibrosis, lung, macrophages, fibroblast, cytokines, endotoxin, asbestos, metals