Epperly M W, Travis E L, Sikora C, Greenberger J S
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Biol Blood Marrow Transplant. 1999;5(4):204-14. doi: 10.1053/bbmt.1999.v5.pm10465100.
Radiation pneumonitis remains a critical dose-limiting toxicity of total body irradiation (TBI) for use in bone marrow transplantation. The acute and chronic phases of radiation damage in the mouse lung have been shown to correlate with mouse strain genotype and are dependent on fraction size, total dose, and total lung volume. Our prior studies demonstrated effective prevention of irradiation-induced lung damage and improved survival in C57BL/6J mice by MnSOD plasmid/liposome gene therapy. In the present studies, we investigated the kinetics of irradiation-induced upregulation of mRNA for acute phase cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, and fibrosis-associated transforming growth factor (TGF)-beta and isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) in 2000 cGy whole-lung irradiated C57BL/6J mice, a strain known to develop dose and volume-dependent organizing alveolitis/fibrosis. The results demonstrate increase in mRNA for IL-1 between days 1 and 14 after irradiation with return to baseline levels out to 120 days. TNF-alpha mRNA levels were not initially elevated but increased between 80 and 100 days and then decreased by 120 days. The mRNA levels for TGF-beta1 demonstrated an initial increase within the first 14 days after total lung irradiation with a decrease to baseline levels out to 100 days. Then, in striking contrast to the other two cytokines, an increase in TGF-beta2 mRNA occurred at around 120 days and correlated with the detection of organizing alveolitis/radiation fibrosis and mortality. These results are consistent with a two-phase mechanism in the molecular pathology of irradiation lung injury, in which IL-1 cytokine mRNA levels correlated with the acute pneumonitis phase and delayed elevation of TNF-alpha (80-100 days), TGF-beta1 (100 days), and TGF-beta2 (120 days) were associated with the fibrosis phase. Insight into the cell-specific and tissue-specific molecular mechanisms of ionizing irradiation induction of mRNA for pulmonary cytokines may provide new strategies for treatment of radiation pneumonitis in TBI patients.
放射性肺炎仍然是骨髓移植中全身照射（TBI）的一种关键剂量限制毒性。小鼠肺部辐射损伤的急性和慢性阶段已被证明与小鼠品系基因型相关，并取决于分次剂量、总剂量和全肺体积。我们之前的研究表明，通过MnSOD质粒/脂质体基因疗法可有效预防C57BL/6J小鼠的辐射诱导肺损伤并提高存活率。在本研究中，我们调查了2000 cGy全肺照射的C57BL/6J小鼠（一种已知会发生剂量和体积依赖性机化性肺泡炎/纤维化的品系）中，辐射诱导的急性期细胞因子白细胞介素（IL）-1和肿瘤坏死因子（TNF）-α以及纤维化相关转化生长因子（TGF）-β及其异构体（TGF-β1、TGF-β2和TGF-β3）mRNA上调的动力学。结果表明，照射后第1天至14天IL-1的mRNA增加，到120天时恢复到基线水平。TNF-α mRNA水平最初未升高，但在80至100天之间升高，然后在120天时下降。TGF-β1的mRNA水平在全肺照射后的前14天内最初升高，到100天时降至基线水平。然后，与其他两种细胞因子形成鲜明对比的是，TGF-β2 mRNA在大约120天时增加，并与机化性肺泡炎/放射性纤维化的检测和死亡率相关。这些结果与辐射性肺损伤分子病理学中的两阶段机制一致，其中IL-1细胞因子mRNA水平与急性肺炎阶段相关，而TNF-α（80 - 100天）、TGF-β1（100天）和TGF-β2（120天）的延迟升高与纤维化阶段相关。深入了解电离辐射诱导肺细胞因子mRNA的细胞特异性和组织特异性分子机制，可能为治疗TBI患者的放射性肺炎提供新策略。
