CHRONIC INFLAMMATION AND IMMUNOMODULATION OF CONNECTIVE TISSUE METABOLISM

单核细胞的募集和激活是启动的核心， 慢性炎性病变的持续和消退。 本实验室的研究继续表征 单核细胞对炎症刺激的趋化性。 一种新发现 趋化性配体是转化生长因子β（TGF β），25，000 MR肽最初是由其诱导转化的能力来定义的。 培养的非肿瘤细胞。 最近，TGF β已被证明 是单核细胞的产物，并诱导快速形成 类似于注射时组织修复中所见的肉芽组织 皮下注射 我们的研究表明，造粒机制， 组织形成可能是TGF β刺激单核细胞的结果 在0.1-1.0 pg/ml的浓度下定向迁移。 的额外 研究表明，单核细胞具有特定的细胞表面受体， 其结合125-I-TGF β。 在较高浓度下，TGF β刺激 单核细胞产生的生长因子，这可能占 与TGF β相关的纤维增生和纤维化反应 注射 定义单核细胞功能激活和调节的其他研究 已经揭示了巨噬细胞的活化诱导IL 2受体基因 表情 这种IL 2受体表达可能具有重要的 免疫调节功能。 在正在进行的研究中，我们已经证明， 单核细胞一旦被募集和激活， 激活因子，刺激成纤维细胞增殖。 中 注射细菌细胞壁诱导的实验动物模型 肝肉芽肿形成，进展为纤维化病变。 的 纤维化是T细胞依赖性的，并且不发生在无胸腺动物中， 用T细胞抑制剂环孢菌素A处理的动物。 这些研究 提供了对细胞和分子机制的深入了解， 免疫介导的结缔组织代谢改变。

Mononuclear cell recruitment and activation are central to the initiation, perpetuation and resolution of chronic inflammatory lesions. Investigations in this laboratory continue to characterize mechanisms of monocyte chemotaxis to inflammatory stimuli. A newly identified chemotactic ligand is transforming growth factor beta (TGFBeta), a 25,000 Mr peptide originally defined by its ability to induce transformation of nonneoplastic cells in culture. More recently, TGFBeta has been shown to be a product of mononuclear cells and to induce the rapid formation of granulation tissue similar to that seen in tissue repair when injected subcutaneously. Our studies indicate that the mechanism of granulation tissue formation may be the consequence of TGFBeta stimulation of monocyte directed migration at concentrations of 0.1-1.0 pg/ml. In additional studies, monocytes were shown to possess specific cell surface receptors which bind 125-I-TGFBeta. At higher concentrations, TGFBeta stimulates monocytes to generate growth factors which may account for the fibroproliferative and fibrogenic response associated with TGFBeta injection. Additional studies defining activation and regulation of monocyte function have revealed that activation of macrophages induce IL2 receptor gene expression. This IL2 receptor expression may have an important immunoregulatory function. In ongoing studies, we have demonstrated that once recruited and activated, mononuclear cells generate fibroblast activating factors which stimulate fibroblast proliferation. In an experimental animal model the injection of bacterial cell walls induces hepatic granuloma formation which progresses to fibrotic lesions. The fibrosis is T cell dependent and does not occur in athymic animals or animals treated with the T cell inhibitor, cyclosporin A. These studies provide insight into the cellular and molecular mechanisms regulating immune-mediated alterations in connective tissue metabolism.