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）：电离辐射诱导的肺损伤限制了肺癌和食管癌治疗中有效的辐射剂量升级。 C57BL/6J小鼠辐射诱导的晚期组织肺泡炎/纤维化的模型紧密遵循人类肺辐照损伤的参数。我们已经证明，在肺部照射后的120-140天，骨髓来源巨噬细胞在加强内皮细胞VCAM-1和ICAM-1时迁移到小鼠肺，然后进行TGF2介导的迁移和骨Marrow骨肌纤维细胞的骨骼肌纤维细胞（骨骼骨膜纤维细胞）造成骨骨间的骨膜/细胞造成骨间骨/细胞造成骨膜细胞/细胞的骨骼。肺内超氧化物歧化酶 - 质粒脂质体（MNSOD-PL）基因治疗可显着降低这两种迁移。现在，我们建议阐明晚期肺部病变启动的细胞和分子机制，并通过MNSOD-PL优化其改善。我们将使用雌性C57BL/6J小鼠和HSV-TK（单纯疱疹病毒 - 胸腺苷激酶）-CCSP+转基因小鼠（具有Ganclovir敏感的Clara细胞分泌蛋白阳性肺部肺干细胞），并且是雄性GFP+骨骨髓的嵌合。第一个特定的目的检验了吸入MNSOD-PL基因治疗的假设通过增强骨髓起源的迁移来促进肺部辐照的假设，从而促进了肺部辐照。第二个特定目的检验了以下假设：周期性重复MNSOD-PL吸入基因治疗通过减少骨髓来源肌纤维细胞的迁移而降低了晚期肺纤维化。第三个特定目的检验了以下假设：将线粒体靶向过氧化酶质粒脂质体吸入到MNSOD-PL将增强肺辐射保护。方法包括MT-catalase-PL的雾化器吸入和肺辐照嵌合小鼠中的MNSOD-PL，通过微型渗透泵，细胞分配和组织病理学连续的BUDR标记。这些研究应定义辐射肺纤维化的关键步骤，并确定治疗性干预的新靶标，从而减少患者的副作用并促进剂量升级，以在初始治疗或恢复复发性胸腔癌中升级。项目叙述 这种辐照应用解决了管理胸部放射疗法的副作用的关键问题 对于肺癌和食道癌。

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