Post BMT Lung Injury Pathophysiology

描述(申请人提供)：大剂量放化疗用于治疗接受骨髓移植的恶性肿瘤患者。最常见的方案仍然是大剂量环磷酰胺(Cy)和全身照射(TBI)，其主要并发症是肺I损伤(称为特发性肺炎综合征：IPS)。死亡率至少为75%。我们已经用Cy/TBI和alIoBMT建立了小鼠模型。肺泡2型(AT2)细胞负责表面活性物质的分泌以及液体和溶质的清除。我们的中心假设是，保存、加速再生或替换AT2细胞的策略将对骨髓移植后的肺修复产生重大影响。细胞因子已被证明可以调节上皮细胞的发育和增殖。成纤维细胞生长因子-7，又称角质形成细胞生长因子，与其受体FGFR2-111B结合，表达于AT2细胞。成纤维细胞生长因子-7对AT2细胞损伤有保护作用。基于AT2是IPS损伤靶点的模型，我们假设成纤维细胞生长因子-7预处理可以预防AT2损伤或促进骨髓移植后AT2细胞的修复，从而减轻IPS损伤。我们的数据表明，成纤维细胞生长因子-7的作用与AT2细胞受损频率的减少有关。在目标1中，我们将以AT2细胞为研究对象，探讨成纤维细胞生长因子-7预防或治疗IPS的作用及其机制(S)。在目标2中，我们将确定细胞疗法是否可以用于预防或治疗IPS损伤。我们推测，骨髓基质细胞(MSCs)，也称为间充质干细胞，或由这些祖细胞分化而来的多能成体祖细胞(MAPC)或AT2细胞，当单独或与成纤维细胞生长因子-7一起使用时，将导致肺泡再上皮化。由于MSCs和MAPC都被证明具有向肺上皮细胞分化的能力，未分化或AT2分化的MSCs和MAPC在骨髓移植后的围骨髓移植中的应用为帮助肺移植后的修复提供了希望。这些可翻译的方法为预防和治疗IPS提供了新的途径。

DESCRIPTION (provided by applicant): High dose chemoradiotherapy is used to treat patients with malignancies undergoing BMT. The most common regimen remains high dose Cytoxan (Cy) and total body irradiation (TBI) which has lung i injury (termed idiopathic pneumonia syndrome: IPS) as a major complication. Mortality is at least 75%.We have established murine models using Cy/TBI and alIoBMT. Alveolar type 2 (AT2) cells are responsible for surfactant secretion and fluid and solute clearance. Our central hypothesis is that strategies that preserve, speed regeneration of, or replace AT2 cells will have a major impact on lung repair post-BMT. Cytokines have been shown to regulate the development and proliferation of epithelial cells. Fibroblast growth factor-7 (fgf-7), also known as keratinocyte growth factor (KGF), binds to its receptor, FgfR2-111b, expressed on AT2 cells. Fgf-7 protects AT2 cells from injury induced. Based on the model that AT2 are targets for IPS injury, we hypothesized that fgf-7 pretreatment would prevent AT2 damage or hasten AT2 cell repair after BMT, reducing IPS injury. Our data indicate fgf-7 effects are associated with a reduced frequency of injured AT2 cells. In aim 1, we will determine the efficacy of and mechanism(s) responsible for the effects of fgf-7 on preventing or treating IPS, focusing upon AT2 cells. In aim 2, we will determine whether cellular therapies can be used to prevent or treat IPS injury. We hypothesize that marrow stromal cells (MSCs), also known as mesenchymal stem cells, or multipotent adult progenitor cells (MAPCs) or AT2 cells differentiated from these progenitor cells will result in alveolar re-epithelialization when used alone or along with fgf-7. Since both MSCs and MAPCs have been shown to have the capacity to differentiate into pulmonary epithelial cells, the peri-BMT administration of undifferentiated or AT2 differentiated MSCs and MAPCs offer promise for aiding in lung repair post-BMT. These translatable approaches offer new avenues for the prevention and treatment of IPS.