Ning Juan, Liu Qi Fa, Luo Xiao Dan, Fan Zhi Ping, Zhang Yu
Department of Hematology, Southern Hospital, Southern Medical University, Guang Zhou, China.
Sci China C Life Sci. 2009 Nov;52(11):1016-22. doi: 10.1007/s11427-009-0139-8. Epub 2009 Nov 24.
To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C(57)BL/6-->BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor alpha (TNFalpha) and Interferon (IFNgamma) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFalpha were lower on day +7 than on day +3. In group B, the levels of TNFalpha attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFalpha were highest on day +7 and there was a significant difference between those on days +7 and +14 (P=0.816). In group A, the levels of IFNgamma on day +7 were higher than on day +3. In group B, the levels of IFNgamma increased progressively, but the comparison of IFNgamma levels in different times had no statistical significance (P=0.521, 0.118, 0.340). In group C, the levels of IFNgamma attained a peak by day +7 and decreased on day +14. aGVHD is the main cause of early non-infectious lung injury. T lymphocytes and TNFalpha are possibly implicated in the pathogenesis of acute GVHD-induced lung injury. The decreased levels of IFNgamma in lung tissues following transplantation might be associated with pulmonary fibrosis in late non-infectious pulmonary complications.
为探讨急性移植物抗宿主病（aGVHD）对异基因造血干细胞移植（allo-HSCT）早期弥漫性肺损伤的影响及发病机制，我们建立了C(57)BL/6→BALB/c小鼠的aGVHD模型。对移植后受体小鼠动态检测胸部计算机断层扫描（CT）、组织病理学以及肺组织中肿瘤坏死因子α（TNFα）和干扰素（IFNγ）等细胞因子水平。单纯照射组（A组）、同基因移植组（B组）和异基因移植组（C组）的aGVHD发生率分别为0%、0%和100%。移植后第3天和第7天，3组受体小鼠的胸部CT扫描均正常。CT显示，A组10只小鼠中有2只在第12天（濒死时）出现双侧肺弥漫性浸润，C组10只小鼠中有6只在第14天（aGVHD发生后3天）出现双侧肺弥漫性浸润，B组移植后第12天和第14天均正常。3组肺组织病理学表现相似，移植后第3天均为轻度间质性肺炎。A组在第7天出现水肿、上皮细胞增生和肺泡间隔增宽，第12天出现上皮细胞坏死、淋巴细胞浸润、出血、蛋白渗漏和局部实变。B组在第7天上皮细胞轻度水肿，较第3天轻，第14天基本正常。C组在第7天表现为毛细血管显著扩张和充血以及淋巴细胞浸润，第14天出现急性肺炎，伴有组织水肿、淋巴细胞和巨噬细胞浸润、蛋白渗漏和血管周围炎症。A组第7天TNFα水平低于第3天。B组TNFα水平在第3天达到峰值，第7天和第14天下降。C组TNFα水平在第7天最高，第7天和第14天之间差异有统计学意义（P=0.816）。A组第7天IFNγ水平高于第3天。B组IFNγ水平逐渐升高，但不同时间IFNγ水平比较无统计学意义（P=0.521、0.118、0.340）。C组IFNγ水平在第7天达到峰值，第14天下降。aGVHD是早期非感染性肺损伤的主要原因。T淋巴细胞和TNFα可能参与急性GVHD诱导的肺损伤发病机制。移植后肺组织中IFNγ水平降低可能与晚期非感染性肺部并发症中的肺纤维化有关。
