ALVEOLAR TYPE II CELL GROWTH IN INJURY

损伤时肺泡 II 型细胞的生长

• 批准号: 2908532
• 负责人: RANDOLPH H HASTINGS
• 金额: $ 20.21万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908532
• 关键词: apoptosis; cell growth regulation; cell proliferation; cytotoxicity; environmental toxicology; laboratory rat; lung injury; parathyroid hormone related protein; respiratory epithelium; respiratory toxin; silicates; tissue /cell culture

Silica causes lung injury and eventual pulmonary fibrosis. Alveolar type I epithelial cell damage and type II epithelial cell proliferation are prominent features of the injury. Our pilot studies show that type II cells undergo apoptosis afer silica injury also. It is widely believed that type II cell proliferation is an important repair process. However, the functional and structural impact of type II cell growth on recovery from silica induced injury has never been defined and the factors that regulate type II cell growth and death after silica exposure are unknown. Our studies suggest that amino terminal and mid-molecule portions of parathyroid regulate these cell after silica-induced lung injury. PTHrP is a pro- hormone that is processed after translation into different daughter peptides with distinct biologic activities. We have found that lung PTHrP expression falls after silica injury in rats, coincident with the onset of type II cell proliferation and apoptosis. Treating rats with exogenous PTHrP 1- 34, the amino-terminal fragment, reduces pneumocyte division (measured by BrdU uptake), while exogenous PTHrP 67-86, a mid-molecule fragment, decreases type II cell apoptosis (measured by TUNEL staining). We hypothesis that the decrease in amino-terminal and mid-proliferation and apoptosis. Furthermore, we believe that an increase in the type II cell population is beneficial in repairing the epithelium, restoring lung architecture and function, and reducing pulmonary fibrosis. Our specific aims are as follows: 1) We will define the structure-function relationships for the effects of PTHrP peptides on the number of type II cells and fibroblasts in the alveoli after silica injury. 3) We will examine the effect of changes in type II cell number on epithelial repair, progression of pulmonary fibrosis and pulmonary structure after silica-induced lung injury. This project will lead to an understanding of the importance of type II cell growth for epithelial repair after silica-induced lung injury and will assess the role of a novel family of growth factors in regulating pneumocyte growth and death. The project will evaluate the potential use of PTHrP-related therapeutic interventions that might speed or improve recovery following silica-induced lung injury.

二氧化硅会导致肺损伤和最终的肺纤维化。 I型I型上皮细胞损伤和II型上皮细胞增殖是损伤的突出特征。我们的试点研究表明，II型细胞也会凋亡伴有二氧化硅损伤。人们普遍认为，II型细胞增殖是一个重要的修复过程。但是，从未定义II型细胞生长对从二氧化硅诱导损伤恢复的功能和结构影响，并且硅胶暴露后调节II型细胞生长和死亡的因素尚不清楚。 我们的研究表明，在二氧化硅诱导的肺损伤后，甲状旁腺的氨基末端和中分子部分调节这些细胞。 PTHRP是一种荷尔蒙，在翻译成具有不同生物学活性的不同女儿肽后进行了处理。我们发现，在大鼠二氧化硅损伤后，肺PTHRP表达下降，与II型细胞增殖和凋亡的发作相吻合。用外源性PTHRP 1-34治疗大鼠氨基末端片段，减少了肺细胞分裂（通过BRDU摄取测量），而外源PTHRP 67-86（一种中型中分子片段）可减少II型细胞凋亡（通过TUNEL染色测量）。我们假设氨基末端和中期差异和细胞凋亡的减少。此外，我们认为，II型细胞群的增加对修复上皮，恢复肺结构和功能以及减少肺纤维化是有益的。我们的具体目的如下：1）我们将定义PTHRP肽对二氧化硅损伤后肺泡中II型细胞数量和成纤维细胞数量的影响的结构 - 功能关系。 3）我们将检查II型细胞数量变化对二氧化硅诱导的肺损伤后肺纤维化的上皮修复，肺纤维化的进展和肺结构的影响。该项目将导致了解II型细胞生长在二氧化硅引起的肺损伤后对上皮修复的重要性，并将评估新型生长因子家族在调节肺细胞生长和死亡中的作用。该项目将评估与PTHRP相关的治疗干预措施的潜在使用，这些干预措施可能会加快二氧化硅引起的肺损伤后加快恢复或改善的恢复。