Mechanisms of lung injury following autologous BMT

自体骨髓移植后肺损伤的机制

• 批准号: 6676506
• 负责人: RODNEY J FOLZ
• 金额: $ 38.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676506
• 关键词: acute disease /disorder; antigen presentation; antigen presenting cell; antioxidants; autologous transplantation; bone marrow transplantation; chemotherapy; fibroblast growth factor; flow cytometry; gene targeting; genetically modified animals; glutathione; inflammation; kinase inhibitor; laboratory mouse; leukocyte activation /transformation; lung injury; lymphocyte; macrophage; monocyte chemoattractant protein 1; oxidative stress; pathologic process; phenotype; protein purification

DESCRIPTION (provided by applicant): Lung toxicity following high dose chemotherapy (HDC) and bone marrow transplantation (BMT) or hematopoietic stem cell support develops in up to 70% of patients, with the most severe form of toxicity, termed idiopathic pneumonia syndrome (IPS), accounting for up to 40% of non-graft versus host disease related deaths. We have described a lung toxicity syndrome that occurs following HDC and autologous bone marrow transplant (autoBMT) that we termed delayed pulmonary toxicity syndrome (DPTS). DPTS may be an early form of IPS, is a risk factor for increased mortality, and manifests as an interstitial pneumonitis no sooner than 4 to 6 weeks following autoBMT (mean onset 11 weeks). To begin to better understand its pathogenesis, we developed a novel HDCIautoBMT mouse model of lung toxicity that shows remarkable similarity to the human condition. Based on clinical and bronchoalveolar lavage studies of patients undergoing HDC/autoBMT and our mouse model, we hypothesize three specific mechanisms the development of DPTS. First, HDC induces an intense oxidative stress resulting in both lung tissue injury and increases in monocyte chemo attractant protein-1 (MCP-1). Second, in response primarily to MCP-1 (and MIP-1a), pulmonary inflammatory cells are recruited into the lung, which possess antigen presenting cells (APC) features and may further stimulate a T cell lymphocyte response. Finally, fibroblast growth factors, like FGF-2, initiate a lung repair and fibrotic response. We plan to test these hypotheses by utilizing mouse strains that 1) overexpress and under express (knockout) antioxidant enzymes, 2) overexpress MCP-1, and 3) are deficient in CCR2. Additional studies designed to characterize the pulmonary inflammatory cells, determine their activation status, and their ability to stimulate T cells will be performed. Finally, we plan to identify BALF growth factors responsible for the development of restrictive lung. This proposal should provide new insights into the pathophysiology of lung injury following autologous bone marrow transplant and provide the basis for future clinical studies to prevent or treat this serious pulmonary complication.

描述（由申请人提供）：高达 70% 的患者在大剂量化疗 (HDC) 和骨髓移植 (BMT) 或造血干细胞支持后出现肺毒性，其中最严重的毒性形式称为特发性肺炎综合征 (IPS)，占非移植物抗宿主病相关死亡的 40%。 我们描述了 HDC 和自体骨髓移植 (autoBMT) 后发生的肺毒性综合征，我们将其称为迟发性肺毒性综合征 (DPTS)。 DPTS 可能是 IPS 的早期形式，是死亡率增加的危险因素，并且在 autoBMT 后 4 至 6 周内表现为间质性肺炎（平均发病时间为 11 周）。 为了更好地了解其发病机制，我们开发了一种新型 HDCIautoBMT 小鼠肺毒性模型，该模型与人类状况显着相似。 基于接受 HDC/autoBMT 的患者的临床和支气管肺泡灌洗研究以及我们的小鼠模型，我们假设了 DPTS 发展的三种具体机制。 首先，HDC 诱导强烈的氧化应激，导致肺组织损伤和单核细胞趋化蛋白-1 (MCP-1) 增加。 其次，主要响应MCP-1（和MIP-1a），肺部炎症细胞被募集到肺部，其具有抗原呈递细胞（APC）特征，并可能进一步刺激T细胞淋巴细胞反应。 最后，成纤维细胞生长因子（如 FGF-2）启动肺部修复和纤维化反应。 我们计划利用以下小鼠品系来测试这些假设：1) 抗氧化酶过度表达和表达不足（敲除），2) 过度表达 MCP-1，3) CCR2 缺陷。 还将进行其他研究，旨在表征肺部炎症细胞、确定其激活状态以及其刺激 T 细胞的能力。 最后，我们计划确定导致限制性肺发育的 BALF 生长因子。 该提案将为自体骨髓移植后肺损伤的病理生理学提供新的见解，并为未来预防或治疗这种严重肺部并发症的临床研究提供基础。