Post BMT Lung Injury Pathophysiology

描述（由申请人提供）：大剂量放化疗用于治疗恶性肿瘤行BMT的患者。最常见的治疗方案仍然是高剂量环磷酰胺（Cy）和全身照射（TBI），其主要并发症是肺损伤（称为特发性肺炎综合征：IPS）。死亡率至少为75%。我们用Cy/TBI和alIoBMT建立了小鼠模型。肺泡2型（AT2）细胞负责表面活性剂的分泌和液体和溶质的清除。我们的中心假设是，保存、加速再生或替换AT2细胞的策略将对肺移植后的肺修复产生重大影响。细胞因子已被证明调节上皮细胞的发育和增殖。成纤维细胞生长因子-7 (fgf-7)，也称为角化细胞生长因子（KGF），与其受体FgfR2-111b结合，在AT2细胞上表达。Fgf-7保护AT2细胞免受损伤。基于AT2是IPS损伤的靶点这一模型，我们假设fgf-7预处理可以预防BMT后AT2损伤或加速AT2细胞修复，从而减轻IPS损伤。我们的数据表明，fgf-7效应与AT2细胞损伤频率降低有关。在目标1中，我们将确定fgf-7在预防或治疗IPS方面的功效和机制，重点是AT2细胞。在目的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。我们假设骨髓基质细胞（MSCs），也称为间充质干细胞，或多能成体祖细胞（MAPCs）或从这些祖细胞分化的AT2细胞在单独使用或与fgf-7一起使用时将导致肺泡再上皮化。由于MSCs和MAPCs已被证明具有分化为肺上皮细胞的能力，因此在bmt前后给予未分化或AT2分化的MSCs和MAPCs有助于bmt后肺修复。这些可翻译的方法为IPS的预防和治疗提供了新的途径。

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.