Mechanism of Irradiation Pulmonary Fibrosis

辐照肺纤维化的机制

基本信息

批准号：
7364772
负责人：
JOEL S GREENBERGER
金额：
$ 29.14万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7364772
关键词：
Adverse effects Alveolar Antioxidants Appendix Bone Marrow Breathing CSF3 gene Cell Separation Cells Clara cell-specific protein Data Dose Dose-Limiting Endothelial Cells Female Fibroblasts Fibrosis Ganciclovir Green Fluorescent Proteins Hamman-Rich syndrome Hematopoietic Stem Cell Mobilization Histopathology Human Hydrogen Peroxide Intercellular adhesion molecule 1 Label Lesion Liposomes Lung Malignant neoplasm of esophagus Malignant neoplasm of thorax Manganese Superoxide Dismutase Manuscripts Marrow Measures Mediating Mesenchymal Stem Cells Methods Mitochondria Molecular Mus Myofibroblast Naphthalene Naphthalenes Nebulizer Patients Plasmids Proliferating Protocols documentation Pulmonary Fibrosis Pump Radiation Radiation Protection Radiation therapy Recurrence Research Retreatment Signal Transduction Simplexvirus Stem cells Stromal Cells Superoxides Techniques Testing Therapeutic Intervention Thymidine Kinase Time Toxic effect Toxin Transcriptional Activation Transgenic Mice Up-Regulation Vascular Cell Adhesion Molecule-1 Virus catalase day gene therapy improved irradiation macrophage male migration mouse model progenitor research study uptake

项目摘要

DESCRIPTION (provided by applicant): Ionizing irradiation-induced pulmonary damage limits effective radiation dose escalation in the treatment of lung and esophageal cancer. The C57BL/6J mouse model of irradiation-induced late organizing alveolitis/fibrosis closely follows the parameters of human pulmonary irradiation damage. We have demonstrated that bone marrow origin macrophages migrate to the mouse lung at the time of up regulation of endothelial cell VCAM-1 and ICAM-1 at 120-140 days after pulmonary irradiation, followed by TGF2-mediated migration and proliferation of bone marrow origin myofibroblast progenitor cells (bone marrow stromal cells/mesenchymal stem cells), which contribute to pulmonary fibrosis. Both migrations are significantly reduced by intrapulmonary manganese superoxide dismutase-plasmid liposome (MnSOD-PL) gene therapy. We now propose to elucidate the cellular and molecular mechanism(s) of initiation of the late pulmonary lesion and optimize its amelioration by MnSOD-PL. We will use female C57BL/6J mice and HSV-TK (Herpes Simplex Virus-Thymidine Kinase)-CCSP+ transgenic mice (which have gancyclovir sensitive Clara Cell Secretory Protein positive lung stem cells) and are chimeric for male GFP+ bone marrow. The first specific aim tests the hypothesis that inhalation MnSOD-PL gene therapy facilitates lung irradiation through enhancement of migration of marrow origin reparative alveolar and bronchial stem cell progenitors. The second specific aim tests the hypothesis that periodic repeat MnSOD-PL inhalation gene therapy decreases late pulmonary fibrosis through decreased migration of marrow origin myofibroblasts. The third specific aim tests the hypothesis that adding inhalation of mitochondrially targeted catalase plasmid liposomes to MnSOD-PL will enhance lung radiation protection. Methods include nebulizer-inhalation of mt-catalase-PL, and MnSOD-PL in pulmonary irradiated chimeric mice, continuous BUDR labeling by mini-osmotic pump, cell sorting, and histopathology. These studies should define critical steps in irradiation pulmonary fibrosis and identify new targets for therapeutic intervention, thereby decreasing patient side effects and facilitating dose escalation in the initial treatment or retreatment of recurrent thoracic cancers.

描述（由申请人提供）：电离辐射引起的肺部损伤限制了肺癌和食道癌治疗中有效辐射剂量的增加。辐射引起的晚期组织性肺泡炎/纤维化的 C57BL/6J 小鼠模型与人类肺辐射损伤的参数密切相关。我们已经证明，在肺部照射后120-140天，当内皮细胞VCAM-1和ICAM-1上调时，骨髓来源的巨噬细胞迁移到小鼠肺部，随后TGF2介导的骨髓来源的迁移和增殖肌成纤维细胞祖细胞（骨髓基质细胞/间充质干细胞），导致肺纤维化。肺内锰超氧化物歧化酶质粒脂质体（MnSOD-PL）基因治疗显着减少了这两种迁移。我们现在建议阐明晚期肺部病变起始的细胞和分子机制，并优化 MnSOD-PL 对其的改善。我们将使用雌性 C57BL/6J 小鼠和 HSV-TK（单纯疱疹病毒胸苷激酶）-CCSP+ 转基因小鼠（具有更昔洛韦敏感的 Clara 细胞分泌蛋白阳性肺干细胞），并且与雄性 GFP+ 骨髓嵌合。第一个具体目标测试了以下假设：吸入 MnSOD-PL 基因疗法通过增强骨髓来源的修复性肺泡和支气管干细胞祖细胞的迁移来促进肺部照射。第二个具体目标测试了以下假设：周期性重复 MnSOD-PL 吸入基因疗法通过减少骨髓来源的肌成纤维细胞的迁移来减少晚期肺纤维化。第三个具体目标测试了以下假设：在 MnSOD-PL 中添加吸入线粒体靶向过氧化氢酶质粒脂质体将增强肺部辐射防护。方法包括在经肺部照射的嵌合小鼠中雾化吸入mt-过氧化氢酶-PL和MnSOD-PL、通过微型渗透泵连续进行BUDR标记、细胞分选和组织病理学。这些研究应确定辐射肺纤维化的关键步骤，并确定治疗干预的新目标，从而减少患者的副作用，并促进复发性胸部癌症的初始治疗或再治疗中的剂量递增。