MCP-1 IN LUNG FIBROSIS

最近的证据表明，这种生物具有潜在的新生物学活性 C-C趋化因子、单核细胞趋化蛋白-1(MCP-1) 趋化性。其上调胶原基因的能力 内源性转化生长因子β1在肺成纤维细胞中的表达 在细胞外基质的积累中可能起重要作用 以肺纤维化为特征。因此，这种C-C趋化因子具有 通过成纤维细胞驱动沉积的潜在能力。因此， 这个项目的中心假设继续集中在 这种趋化因子在介导肺纤维化的重要信号中起着重要作用。 具体地说，最初由嗜酸性粒细胞和其他细胞分泌的MCP-1 推测在上调TGFbeta1的表达中起重要作用 成纤维细胞，可能还有其他肺细胞，导致分化 成纤维细胞向肌成纤维细胞的转化以及对胶原合成的刺激。 肌成纤维细胞随后表达MCP-1有可能 以自分泌的方式传播这些效应。该试验计划将 抗单核细胞趋化蛋白-1抗体对博莱霉素诱导的影响 肺部炎症、细胞因子表达与纤维化，要看什么 细胞因子是肺肌成纤维细胞细胞因子的上游调节因子 和胶原基因的表达。MCP-1 TGFbeta1之间的组网将 通过研究体内中和一种细胞因子的效果来检验 使用特异性抗体并监测其对肺组织表达的影响 另一种细胞因子。嗜酸性粒细胞MCP-1表达的调节将是 审查以评价负责的调解人，作为提供 深入了解MCP-1的调节机制。C-C趋化因子受体(S) (CC-CKR)将参与介导MCP-1对成纤维细胞的影响 鉴定，并评价其在博莱霉素损伤肺和肺组织中的表达 从这些肺中分离出的细胞。同一性及其功能意义 这些受体中的一种将使用从选择性地 CC-CKR基因敲除小鼠及其在肝纤维化中的作用 在这些小鼠身上建立博莱霉素模型。鉴于其独特的重要性， 肌成纤维细胞，将特别关注可能的 该细胞对已鉴定受体(S)的差异表达 相对于未分化的成纤维细胞。实现这些目标应 阐明MCP-1在肺纤维化中的多方面作用，并提供 进一步深入了解与慢性炎症相关的关键机制 纤维化。

Recent evidence suggests potentially novel biological activities for the C-C chemokine, monocyte chemotactic protein-1 (MCP-1) beyond its chemotactic properties. Its ability to up-regulate collagen gene expression in lung fibroblasts mediated by endogenous TGFbeta1, suggests a potentially important role in the accumulation of extracellular matrix characteristic of pulmonary fibrosis. Thus this C-C chemokine has the potential ability to drive the deposition by fibroblasts. Hence the central hypothesis of this project continues to be focussed on the role of this chemokine in mediating important signals for pulmonary fibrosis. Specifically, MCP-1 initially secreted by eosinophils and other cells, is hypothesized to be important in up-regulating TGFbeta1 expression in fibroblasts and perhaps other lung cells, resulting in the differentiation of fibroblasts to myofibroblasts and stimulation of collagen synthesis. Subsequent MCP-1 expression by myofibroblasts has the potential of propagating these effects in autocrine fashion. The experimental plan will investigate the effects of anti-MCP-1 antibodies on bleomycin-induced pulmonary inflammation, cytokine expression and fibrosis, to see what cytokines are upstream to the regulation of lung myofibroblast cytokine and collagen gene expression. The networking between MCP-1 TGFbeta1 will be examined by studying the effects of neutralizing one cytokine in vivo using specific antibodies and monitoring the effects on lung expression of the other cytokine. The regulation of eosinophil MCP-1 expression will be examined to evaluate the mediators responsible as a means of providing insight into the MCP-1 mediate mechanism. The C-C chemokine receptor(s) (CC-CKR) involved in mediating the MCP-1 effects on fibroblasts will be identified, and their expression evaluated in bleomycin-injured lungs and cells isolated from those lungs. The identity and functional significance of these receptors will be confirmed using cells isolated from selective CC-CKR knockout mice and their role in fibrosis examined by applying the bleomycin model on these mice. Given the unique importance of the myofibroblast, special attention will be focussed on the possible differential expression of the identified receptor(s) by this cell vis-a- vis the undifferentiated fibroblast. Attainment of these aims should clarify the multifaceted roles of MCP-1 in pulmonary fibrosis, and provide further insight into key mechanisms, which relate chronic inflammation to fibrogenesis.