ALVEOLAR TYPE II CELL GROWTH IN INJURY

二氧化硅导致肺损伤并最终导致肺纤维化。肺泡I型上皮细胞损伤和II型上皮细胞增生是损伤的显著特征。我们的初步研究表明，II型细胞在二氧化硅损伤后也会发生凋亡。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损伤后恢复的功能和结构影响尚未明确，二氧化硅暴露后调节II型细胞生长和死亡的因素尚不清楚。我们的研究表明，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，在被翻译成具有不同生物活性的子肽后被加工。我们发现大鼠肺PTHrP表达在二氧化硅损伤后下降，与II型细胞增殖和凋亡的开始一致。用外源性PTHrP 1- 34（氨基末端片段）处理大鼠，减少肺细胞分裂（通过BrdU摄取测量），而外源性PTHrP 67-86（中间分子片段）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，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II型细胞和成纤维细胞数量影响的结构-功能关系。3)我们将研究II型细胞数量的变化对二氧化硅诱导肺损伤后上皮修复、肺纤维化进展和肺结构的影响。该项目将有助于了解II型细胞生长对二氧化硅诱导肺损伤后上皮修复的重要性，并将评估一个新的生长因子家族在调节肺细胞生长和死亡中的作用。该项目将评估与pthrp相关的治疗干预措施的潜在用途，这些干预措施可能会加速或改善二氧化硅诱导肺损伤后的恢复。

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.