Mechanisms of lung injury following autologous BMT

描述（由申请方提供）：高达70%的患者在高剂量化疗（HDC）和骨髓移植（BMT）或造血干细胞支持后发生肺毒性，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高达40%。 我们描述了一种发生在HDC和自体骨髓移植（autoBMT）后的肺毒性综合征，我们称之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，并在自体BMT后4 - 6周内表现为间质性肺炎（平均发病11周）。 为了开始更好地了解其发病机制，我们开发了一种新的HDCI autoBMT小鼠肺毒性模型，该模型显示出与人类状况的显著相似性。 基于对接受HDC/autoBMT的患者和我们的小鼠模型的临床和支气管肺泡灌洗研究，我们假设DPTS的发展有三种特定机制。 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）的增加。 其次，主要响应于MCP-1（和MIP-1a），肺部炎症细胞被募集到肺中，其具有抗原呈递细胞（APC）特征，并且可以进一步刺激T细胞淋巴细胞应答。 最后，成纤维细胞生长因子，如FGF-2，启动肺修复和纤维化反应。 我们计划通过利用小鼠品系来测试这些假设，所述小鼠品系1）过表达和表达不足（敲除）抗氧化酶，2）过表达MCP-1，和3）缺乏CCR 2。 将进行旨在表征肺部炎症细胞、确定其活化状态及其刺激T细胞的能力的其他研究。 最后，我们计划确定BALF生长因子负责发展限制性肺。 这一建议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的肺部并发症的临床研究提供基础。

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.