Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Am J Respir Cell Mol Biol. 2011 Jul;45(1):127-35. doi: 10.1165/rcmb.2010-0265OC. Epub 2010 Sep 24.
Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1.
接受胸部放射治疗的患者常发生肺损伤和纤维化。目前，尚无有效的预防或治疗这些疾病的措施。我们测试了阻断趋化因子 C-C 型趋化因子配体（CCL）3 及其受体 C-C 型趋化因子受体（CCR）1 和 CCR5 是否能预防放射性肺炎症和纤维化。采用遗传技术或药物干预阻断 C57BL/6J 小鼠的 CCL3 与 CCR1 或 CCR5 的相互作用，使 C57BL/6J 小鼠接受胸部放射治疗。通过肺组织组织化学染色和流式细胞术评估肺炎症，通过羟脯氨酸测定和胶原染色测量纤维化，并通过侵袭性程序研究肺功能。缺乏 CCL3 或其受体 CCR1 的照射小鼠未发生照射野生型小鼠所见的肺炎症、纤维化和肺功能下降。用 CCR1 的小分子抑制剂对野生型小鼠进行药物治疗也可预防肺炎症和纤维化。相比之下，缺乏 CCR5 的小鼠不能免受辐射引起的损伤和纤维化的影响。CCL3 与其受体 CCR1 的选择性相互作用对于放射性肺炎症和纤维化至关重要，而 CCR1 的小分子抑制剂可大大预防这些疾病。
