Mast cells in acute and chronic rejection of rat cardiac allografts -: A major source of basic fibroblast growth factor
Mast cells in acute and chronic rejection of rat cardiac allografts -: A major source of basic fibroblast growth factor
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DOI：
10.1097/00007890-200106270-00007
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发表时间：
2001-06-27
期刊：
影响因子：
6.2
通讯作者：
Lemström, KB
中科院分区：
文献类型：
--
作者：
Koskinen, PK;Kovanen, PT;Lemström, KB
背景，心脏移植物动脉硬化的研究，慢性排斥主要集中在血管壁和闭塞血管周围的单核炎性细胞浸润。本研究旨在探讨肥大细胞在大鼠心脏移植急性和慢性排斥反应发生中的作用。在急性排斥模型中，移植受者未接受免疫抑制剂治疗，移植后5天在发生严重急性排斥时取出移植物。在慢性排斥反应模型中，受体给予三联免疫抑制剂，移植后90天取出移植物。在急性排斥反应中，肥大细胞的数量没有增加，但定位模式不同于同系移植物。在急性排斥反应中，肥大细胞位于同种异体移植物的血管周围区域，但在同系移植物中，肥大细胞具有更多的间质位置。在慢性排斥反应模型中，移植心脏内膜严重增厚，在闭塞的心肌内血管周围和内膜中可见大量肥大细胞，直线回归分析显示血管周围和间质肥大细胞数量与内膜增厚程度显著相关。多数肥大细胞对碱性成纤维细胞生长因子（bFGF）呈阳性反应。巨噬细胞bFGF的表达不那么突出，但巨噬细胞的数量更频繁。肿瘤坏死因子-α的表达主要在巨噬细胞和少数肥大细胞中检测到。当动脉硬化的强度通过增加免疫抑制的强度而降低时，移植物内肥大细胞和其他单核细胞的数量以及它们各自的细胞因子bFGF和肿瘤坏死因子-α的产生逐渐减少。两者合计，我们的数据表明，心肌内肥大细胞浸润的强度与慢性炎症和同种异体移植物动脉炎的变化，但不与急性排斥反应的强度，肥大细胞，除了巨噬细胞，是心肌bFGF的主要来源，该结果还表明，当T细胞活化途径被环孢菌素阻断，肥大细胞的数量减少。环孢菌素可能影响了细胞因子的产生，从而干扰了肥大细胞依赖性启动以及肥大细胞-白细胞因子级联影响的免疫应答的白细胞和肥大细胞依赖性扩增和进展。肥大细胞产生的碱性成纤维细胞生长因子可能促进心脏移植物动脉硬化过程中的炎症、新生血管和纤维化。
Background, Studies of cardiac allograft arteriosclerosis, i.e., chronic rejection, have largely focused on mononuclear inflammatory cell infiltrates in the vascular wall and periphery of the occluded vessels. The purpose of this study was to investigate the role of mast cells in the development of acute and chronic rejection in rat cardiac allografts.Methods. In the acute rejection model, transplant recipients were not treated with immunosuppressants, and the grafts were removed 5 days after transplantation at the time of severe acute rejection. In the chronic rejection model, the recipients were administered triple-drug immunosuppression, and the grafts were removed 90 days after transplantation.Results. During acute rejection, the number of mast cells was not increased, but the localization pattern differed from that of syngeneic grafts. In acute rejection, mast cells were located in the perivascular region of the allografts, but in syngeneic grafts, mast cells had a more interstitial location. In the chronic rejection model, the cardiac allografts with severe intimal thickening showed large numbers of mast cells at perivascular sites of occluded intramyocardial vessels and in the interstitium, Linear regression analysis revealed a significant correlation between the numbers of perivascular and interstitial mast cells and the intensity of intimal thickening. The majority of mast cells showed positive immunoreactivity to basic fibroblast growth factor (bFGF). Macrophage bFGF expression was not so prominent, but macrophages were more frequent in numbers. Tumor necrosis factor-alpha expression was detected mainly in macrophages and in only a few mast cells. When the intensity of arteriosclerosis was decreased by an increase in the intensity of immunosuppression, the numbers of intragraft mast cells and other mononuclear cells, and also the production of their respective cytokines, bFGF and tumor necrosis factor-alpha, gradually diminished.Conclusions. Taken together, our data show that the intensity of intramyocardial mast cell infiltration was associated with the intensity of chronic inflammation and allograft arteriosclerotic changes, but not with acute rejection, and that mast cells, in addition to macrophages, are a major source of myocardial bFGF, The results also demonstrate that when the T-cell activation pathway is blocked using cyclosporin, the number of mast cells is decreased. Cyclosporin may have affected the cytokine production that interfered with both the mast cell-dependent initiation and the leukocyte- and mast cell-dependent amplification and progression of the immune responses influenced by mast cell-leukocyte cytokine cascades. bFGF produced by mast cells may contribute to enhanced inflammation, neovascularization, and fibrosis during cardiac allograft arteriosclerosis.