MECHANISMS OF PARTICLE-INDUCED LUNG DISEASE

工作总结：各种人造颗粒，当吸入时，是纤维增生性肺部疾病的来源。这些疾病的一个关键特征是肺内结缔组织细胞的过度增殖。我们推测血小板衍生生长因子（PDGF）受体系统是这些疾病的进展的关键。致纤维化颗粒引起肺损伤并刺激巨噬细胞产生炎症介质，如白细胞介素-1 β（IL-1 β）、转化生长因子β-1（TGF-β-1）和前列腺素E2（PGE2），这些介质调节PDGF受体表达。我们发现IL-1 β上调PDGF α受体，增加肺成纤维细胞对PDGF的促有丝分裂和趋化反应。相反，TGF-β 1和PGE2下调PDGF受体系统并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剂是内毒素和金属如钒。在钒诱导的大鼠肺损伤后体内发生PDGF α受体的诱导，并先于成纤维细胞增生。IL-1 β诱导的PDGF α受体的体外表达依赖于p38 MAP激酶，而不依赖于细胞外信号调节激酶（ERK）或c-Jun N-末端激酶（JNKs）。（p50/p65蛋白）通过凝胶位移/超位移和IkB-α的协调降解，提示IL-1 β似乎不通过经典的NF κ B途径诱导PDGF受体。今后的工作将侧重于：1）阐明介导PDGF受体上调的转录因子和2）可溶性细胞外PDGF受体的过表达以抑制大鼠和小鼠中肺纤维化的进展。预计这项研究将导致干预肺纤维增生性肺病的策略。- 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