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.
| Yang, Meng; Burton, Doug W; Geller, Jack et al. (2006) The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model. Clin Cancer Res 12:2602-6 |
| Burton, D W; Geller, J; Yang, M et al. (2005) Monitoring of skeletal progression of prostate cancer by GFP imaging, X-ray, and serum OPG and PTHrP. Prostate 62:275-81 |
| Hastings, Randolph H; Folkesson, Hans G; Matthay, Michael A (2004) Mechanisms of alveolar protein clearance in the intact lung. Am J Physiol Lung Cell Mol Physiol 286:L679-89 |
| Hastings, Randolph H (2004) Parathyroid hormone-related protein and lung biology. Respir Physiol Neurobiol 142:95-113 |
| Hastings, Randolph H; Araiza, Flavio; Burton, Douglas W et al. (2004) Role of parathyroid hormone-related protein in lung cancer cell survival. Chest 125:150S |
| Hastings, Randolph H; Araiza, Flavio; Burton, Douglas W et al. (2004) Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A. Am J Physiol Cell Physiol 287:C1616-22 |
| Hastings, Randolph H; Quintana, Rick A; Sandoval, Rebeca et al. (2003) Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung. Am J Physiol Lung Cell Mol Physiol 285:L1312-22 |
| Hastings, Randolph H; Araiza, Flavio; Burton, Douglas W et al. (2003) Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells. Am J Physiol Cell Physiol 285:C1429-36 |
| Hastings, Randolph H; Quintana, Rick A; Sandoval, Rebeca et al. (2003) Proapoptotic effects of parathyroid hormone-related protein in type II pneumocytes. Am J Respir Cell Mol Biol 29:733-42 |
| Hastings, Randolph H; Asirvatham, Angela; Quintana, Rick et al. (2002) Parathyroid hormone-related protein-(38-64) regulates lung cell proliferation after silica injury. Am J Physiol Lung Cell Mol Physiol 283:L12-21 |
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