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Title: [The roles of TSP-1 and its receptor CD47 in pathogenesis of paraquat-induced pulmonary fibrosis in rats].
Author: Zhang J, Liu KX, Gao W, Xie XS.
Journal: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi; 2017 Dec 20; 35(12):881-887. PubMed ID: 29495147.
Abstract:
Objective: To establish a rat model of paraquat (PQ) -induced pulmonary fibrosis and observe the changes in thrombospondin-1 (TSP-1) and its receptor CD47 in lung tissue, and to investigate their roles in the pathogenesis of PQ-induced pulmonary fibrosis. Methods: Fifty-four clean adult male Sprague-Dawley rats were randomly divided into normal control group (n=6) and 2 h, 12 h, 1 d, 3 d, 7 d, and 14 d PQ poisoning groups (n=8 per group). A rat model of PQ poisoning was established by a single gavage of 20 wt.% PQ solution (50 mg/kg). Flow cytometry was used to determine the concentration of reactive oxygen species (ROS) in blood and lung tissue. Enzyme-linked immunosorbent assay was used to determine the concentrations of hydroxyl radicals, malondialdehyde, and hydroxyproline in lung tissue. HE staining and Masson staining were used to observe the pathological damage of lung tissue after PQ poisoning. The expression of TSP-1 and CD47 in lung tissue was measured by Immunohistochemistry. Results: Compared with the normal control group, the 2 h to 7 d PQ poisoning groups showed significant increases in ROS fluorescence intensity in red blood cells and lung tissues and the concentrations of malondialdehyde and hydroxyl radicals in lung tissue (P<0.05) , and the 14 d PQ poisoning group had a significant increase in the concentration of hydroxyproline in lung tissue (P<0.05). HE staining showed that the 2 h to 7 d PQ poisoning groups had significantly higher semiquantitative pathological scores of pulmonary alveolitis than the normal control group (P<0.05). The Masson staining showed that the 7 d and 14 d PQ poisoning groups had significantly higher semiquantitative pathological scores of pulmonary fibrosis than the normal control group (P<0.05). Compared with the normal control group, all PQ poisoning groups (except the 12 h group) had significantly increased expression of TSP-1 in lung tissue (P<0.05) , and all PQ poisoning groups (except the 1 d group) had significantly increased expression of CD47 in lung tissue (P<0.05). Within 2 h after PQ poisoning, the expression of TSP-1 and CD47 was positively correlated with the concentrations of ROS, hydroxyl radicals, and malondialdehyde and the degree of pulmonary alveolitis (P<0.01) ; at 1 d after PQ poisoning, the expression of TSP-1 and CD47 was positively correlated with the concentration of hydroxyproline in lung tissue (P<0.01) . Conclusion: The expression of TSP-1 and CD47 is closely related to oxidative stress and subsequent pulmonary fibrosis, and they may be involved in the development and progression of pulmonary alveolitis and subsequent pulmonary fibrosis in rats with PQ poisoning. 目的： 构建百草枯（PQ）肺纤维化大鼠模型，观察血小板反应蛋白-1（TSP-1）及其受体CD47在肺组织中的分布及变化，并探讨其在PQ肺纤维化发病机制中的作用。 方法： 将54只成年清洁级雄性SD大鼠，随机分为正常对照组（n=6）、PQ染毒组（n=48），PQ染毒组下设2 h、12 h、1 d、3 d、7 d和14 d共6个时间点，每个时间点各8只大鼠。使用质量分数为20%的PQ溶液50 mg/kg一次性灌胃大鼠建立PQ中毒模型。通过流式细胞仪检测大鼠血液和肺组织活性氧（ROS）浓度；酶联免疫吸附法测定肺组织中羟自由基、丙二醛和羟脯氨酸浓度；HE染色和Masson染色观察PQ中毒后肺组织病理损害；免疫组织化学法观察TSP-1及CD47蛋白在肺组织中的表达。 结果： 与正常对照组相比，PQ染毒2 h至7 d组大鼠血红细胞和肺组织中ROS荧光强度阳性率比值升高，差异均有统计学意义（P<0.05）。与正常对照组相比，PQ染毒2 h至7 d组大鼠肺组织中丙二醛和羟自由基浓度明显升高，差异均有统计学意义（P<0.05），PQ染毒14 d组大鼠肺组织中羟脯氨酸浓度明显升高，差异均有统计学意义（P<0.05）。HE染色结果显示，与正常对照组相比，PQ染毒2 h至7 d组大鼠肺组织的肺泡炎半定量病理评分升高，差异均有统计学意义（P<0.05）；Masson染色结果显示，与正常对照组相比，PQ染毒7 d和14 d组大鼠肺组织的肺纤维化半定量病理评分明显升高，差异均有统计学意义（P<0.05）。与正常对照组相比，各PQ染毒组（除染毒12 h组外）大鼠肺组织TSP-1的表达水平升高，差异均有统计学意义（P<0.05）；各PQ染毒组（除染毒1 d组外）大鼠肺组织CD47的表达水平升高，差异均有统计学意义（P<0.05）。相关性分析发现，在PQ中毒2 h内，TSP-1和CD47的表达量与ROS、羟自由基和丙二醛浓度及肺泡炎程度均呈正相关（P<0.01）；在PQ中毒1 d后，TSP-1和CD47的表达量与肺组织羟脯胺酸浓度均呈正相关（P<0.01）。 结论： TSP-1-CD47的表达与早期氧化应激及后期肺纤维化密切相关，可能参与了PQ中毒大鼠肺泡炎及肺纤维化的发生发展。.

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