ALVEOLAR TYPE II CELL GROWTH IN INJURY

损伤时肺泡 II 型细胞的生长

• 批准号: 6524796
• 负责人: RANDOLPH H HASTINGS
• 金额: $ 21.28万
• 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/6524796
• 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.

二氧化硅导致肺损伤和最终的肺纤维化。肺泡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。我们的初步研究表明，II型细胞发生凋亡后二氧化硅损伤也。人们普遍认为，II型细胞增殖是一个重要的修复过程。然而，II型细胞生长对二氧化硅诱导的损伤恢复的功能和结构影响从未被定义，并且在二氧化硅暴露后调节II型细胞生长和死亡的因素是未知的。 我们的研究表明甲状旁腺的氨基末端和中分子部分在二氧化硅诱导的肺损伤后调节这些细胞。PTHrP是一种前激素，其在翻译成具有不同生物活性的不同子肽后被加工。我们已经发现，肺PTHrP的表达下降福尔斯后，二氧化硅损伤大鼠，符合II型细胞增殖和凋亡的发病。用外源性PTHrP 1- 34（氨基末端片段）治疗大鼠减少了肺细胞分裂（通过BrdU摄取测量），而外源性PTHrP 67-86（中分子片段）减少了II型细胞凋亡（通过TUNEL染色测量）。我们假设氨基末端和中期增殖和凋亡的减少。此外，我们认为II型细胞群的增加有利于修复上皮，恢复肺结构和功能，并减少肺纤维化。我们的具体目标如下：1）我们将确定PTHrP肽对二氧化硅损伤后肺泡中II型细胞和成纤维细胞数量的影响的结构-功能关系。3)我们将研究二氧化硅诱导的肺损伤后II型细胞数量的变化对上皮修复、肺纤维化进展和肺结构的影响。该项目将导致对二氧化硅诱导的肺损伤后上皮修复的II型细胞生长的重要性的理解，并将评估一种新的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PTHrP相关治疗干预的潜在用途，这些干预可能加速或改善二氧化硅诱导的肺损伤后的恢复。