REGULATING HYALURONAN INDUCED GENES IN LUNG MACROPHAGE

巨噬细胞在炎症和纤维化中发挥重要作用 释放包括活性氧和氮在内的各种介质 物种、蛋白酶和细胞因子。巨噬细胞的调控机制 人们对慢性炎症状态下的激活知之甚少。一个 慢性炎症和纤维化的特征是产生量增加 细胞外基质(ECM)的周转。透明质酸(HA)是一种 炎症部位产生的糖胺聚糖细胞外基质成分。 肺部炎症和纤维化与积聚的 肺间质中有透明质酸碎片。我们之前已经证明，HA 片段，而不是自然的前体，诱导数字的表达 炎症基因，包括细胞因子家族的几个成员。 这项建议的目的是研究分子机制。 调节HA诱导的肺泡巨噬细胞趋化因子表达。我们 打算通过以下方式做到这一点：1)定义顺位代理 在启动子中传递对HA片段的反应性的元件 趋化因子基因RANTES和IP-10(CRG-2)；2)定义 抑制HA片段诱导巨噬细胞炎症表达的实验研究 小鼠原代骨髓中IL-10和γ-干扰素诱导的多肽-1α 细胞；30以确定γ-干扰素和IL-10对HA的影响 片段诱导肺泡巨噬细胞趋化因子的表达 来自博莱霉素处理的小鼠。

Macrophages play an essential role in inflammation and fibrosis through the release of a variety of mediators including reactive oxygen and nitrogen species, proteases, and cytokines. The mechanisms regulating macrophage activation in chronic inflammatory states are poorly understood. A hallmark of chronic inflammation and fibrosis is the increased production and turnover of the extracellular matrix (ECM). Hyaluronan (HA) is a glycosaminoglycan ECM component produced at sites of inflammation. Pulmonary inflammation and fibrosis are associated with the accumulation of HA fragments in the lung interstitium. We have previously shown that HA fragments, but not the native precursor, induce the expression of a number of inflammatory genes including several members of the cytokine family. The purpose of this proposal is to investigate the molecular mechanisms regulating HA-induced chemokine expression in alveolar macrophages. We intend to do so in the following manner: 1) to define the cis-acting elements that convey responsiveness to HA fragments in the promotors of the chemokine genes RANTES and IP-10 (crg-2); 2) to define the mechanism for the inhibition of HA-fragment-induced expression of macrophage Inflammatory Peptide-1alpha by IL-10 and gamma-interferon in mouse primary bone marrow cells; 30 to determine the effects of gamma-interferon and il-10 on HA fragment-induced expression of chemokines in alveolar macrophages isolated from bleomycin-treated mice.