Mechanism of Irradiation Pulmonary Fibrosis

辐照肺纤维化的机制

• 批准号: 8270375
• 负责人: JOEL S GREENBERGER
• 金额: $ 28.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8270375
• 关键词: Address; Adverse effects; Alveolar; Antioxidants; Bone Marrow; Breathing; CSF3 gene; Cell Separation; Cells; Chest; Clara cell-specific protein; Data; Dose; Dose-Limiting; Endothelial Cells; Female; Fibroblasts; Fibrosis; Ganciclovir; 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 lung; Malignant neoplasm of thorax; Manganese Superoxide Dismutase; Manuscripts; Marrow; Measures; Mediating; Mesenchymal Stem Cells; Methods; Mitochondria; Molecular; Mus; Myofibroblast; Naphthalene; Nebulizer; Non-Small-Cell Lung Carcinoma; 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; Transgenic Mice; Up-Regulation; Vascular Cell Adhesion Molecule-1; catalase; gene therapy; improved; irradiation; macrophage; male; migration; mouse model; progenitor; research study; uptake

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. Project Narrative This irradiation application addresses a critical problem in managing the side effects of thoracic radiotherapy for lung and esophagus cancer.

描述（由申请人提供）：电离辐射引起的肺损伤限制了肺癌和食管癌治疗中有效辐射剂量的增加。C57BL/6J小鼠辐照致晚期组织性肺泡炎/纤维化模型与人肺辐照损伤参数基本一致。我们已经证明，在肺照射后120-140天，内皮细胞VCAM-1和ICAM-1上调时，骨髓源性巨噬细胞迁移到小鼠肺部，随后tgf2介导的骨髓源性肌成纤维祖细胞（骨髓基质细胞/间充质干细胞）的迁移和增殖，有助于肺纤维化。肺内锰超氧化物歧化酶质粒脂质体（MnSOD-PL）基因治疗可显著减少这两种迁移。我们现在建议阐明晚期肺病变开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），并与雄性GFP+骨髓嵌合。第一个具体目的是验证吸入MnSOD-PL基因治疗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照射的假设。第二个特定目的是验证周期性重复MnSOD-PL吸入基因治疗通过减少骨髓源肌成纤维细胞的迁移来减少晚期肺纤维化的假设。第三个具体目的是验证在MnSOD-PL中加入线粒体靶向过氧化氢酶质粒脂质体可增强肺辐射防护的假设。方法包括雾化吸入mt-过氧化氢酶- pl和MnSOD-PL，微渗透泵连续标记BUDR，细胞分选和组织病理学检查。这些研究应该确定辐照肺纤维化的关键步骤，确定治疗干预的新靶点，从而减少患者的副作用，促进复发性胸部癌症初始治疗或再治疗的剂量增加。项目的叙述

项目成果

Reduced irradiation pulmonary fibrosis and stromal cell migration in Smad3-/- marrow chimeric mice.

• 发表时间: 2006-09
• 期刊: In vivo
• 影响因子: 2.3
• 作者: M. Epperly;D. Franicola;Xi-chen Zhang;S. Nie;Hong Wang;A. Bahnson;D. Shields;J. Goff;Hongmei Shen;J. Greenberger