MODULATION OF ALVEOLAR MACROPHAGE DRIVEN FIBROBLAST PROLIFERATION BY ALTERNATIVE MACROPHAGE MEDIATORS
MODULATION OF ALVEOLAR MACROPHAGE DRIVEN FIBROBLAST PROLIFERATION BY ALTERNATIVE MACROPHAGE MEDIATORS
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DOI：
10.1172/jci112364
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发表时间：
1986-03-01
影响因子：
15.9
通讯作者：
CRYSTAL, RG
中科院分区：
文献类型：
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作者：
BITTERMAN, PB;WEWERS, MD;CRYSTAL, RG
组织纤维化部分是由于单核吞噬细胞和成纤维细胞释放的生长调节分子之间的相互作用所致。在慢性间质性肺疾病中，已知肺泡巨噬细胞（肺的单核吞噬细胞）自发地释放两种成纤维细胞生长因子，纤连蛋白和肺泡巨噬细胞衍生生长因子（AMDGF），它们一起刺激非复制性肺成纤维细胞分裂。除了这两种主要的生长促进信号之外，肺泡巨噬细胞能够释放其它介质，所述介质可能在响应于这些主要信号而调节肺成纤维细胞复制中具有潜在作用，包括干扰素γ。（IFN γ），前列腺素E2（PGE 2）和白细胞介素1（IL-1）。为了评估这种可能性，我们研究了这些其他介质对肺成纤维细胞复制的影响，在无血清的，确定的培养基中的纤连蛋白和AMDGF。IFN.gamma.对成纤维细胞复制无影响。相反，PGE 2对纤维连接蛋白和AMDGF的成纤维细胞复制产生剂量依赖性抑制，当PGE 2浓度< 10 ng/ml时，观察到最大抑制的50%。虽然IL-1作为初级生长促进信号没有活性，但在4-10 U/ml浓度下，响应于纤连蛋白和AMDGF，IL-1使成纤维细胞复制增加10 - 15%。从时间上看，IL-1的生长促进作用发生在细胞周期G1期的早期。 这些数据表明，肺成纤维细胞复制响应于由间质性肺病中的肺泡巨噬细胞自发释放的两种初级生长促进信号，而不受IFN γ影响，可被PGE 2抑制，并被IL-1适度增强。了解慢性间质性疾病肺泡微环境中相关的成纤维细胞生长调节信号可能会导致合理的治疗策略，旨在中断纤维化过程。
Tissue fibrosis results, in part, from an interaction between growth regulatory molecules released by mononuclear phagocytes and fibroblasts. In the chronic interstitial lung disorders, alveolar macrophages, the mononuclear phagocytes of the lung, are known to spontaneously release two growth factors for fibroblasts, fibronectin and alveolar macrophage-derived growth factor (AMDGF) that together stimulate nonreplicating lung fibroblasts to divide. In addition to these two primary growth promoting signals, alveolar macrophages are able to release other mediators that may have a potential role in modulating lung fibroblast replication in response to these primary signals, including interferon .gamma. (IFN.gamma.), prostaglandin E2 (PGE2), and interleukin 1 (IL-1). To evaluate this possibility, we examined the effect of each of these other mediators on lung fibroblast replication in response to fibronectin and AMDGF in serum-free, defined medium. IFN.gamma. had no effect on fibroblast replication. In contrast, PGE2 resulted in a dose-dependent inhibition of fibroblast replication in reponse to fibronectin and AMDGF with 50%of the maximum inhibition observed at a PGE2 concentration of < 10 ng/ml. IL-1, while not active as a primary growth promoting signal, at concentrations of 4-10 U/ml, augmented fibroblast replication in response to fibronectin and AMDGF by 10 to 15%. Temporally, the growth augmenting effect of IL-1 occurred early in the G1 phase of the cell cycle. These data indicate that lung fibroblast replication in response to two of the primary growth promoting signals spontaneously released by alveolar macrophages in the interstitial lung disorders, while uninfluenced by IFN.gamma., can be inhibited by PGE2 and modestly augmented by IL-1. Understanding the relevant fibroblast growth modulatory signals within the alveolar microenvironment in the chronic interstitial disorders may lead to rational therapeutic strategies designed to interrupt the fibrotic process.