Parathyroid hormone-related protein (PTHrP) plays important roles in regulating a variety of developmental processes in many organs, through paracrine, autocrine and intracrine pathways. Conventional knockout of PTHrP in mice results in neonatal lethal with multiple defects including asphyxia, skeletal deformities and osteochondrodysplasia. In the present study, PTHrP conditional knockout in mouse lung epithelia versus mesenchyme has been generated. Abrogation of PTHrP specifically in lung mesenchyme results in a neonatal lethal due to lung alveolarization arrest and respiratory failure accompanied with diminished cell proliferation, loss of myofibroblasts and increased elastin accumulation. These manifestations are similar to those observed in bronchopulmonary dysplasia. No abnormality has been found in PTHrP epithelial-specific knock-out mice. Therefore, we conclude that PTHrP expression in lung mesenchyme, but not in epithelia, is essential for postnatal lung development, possibly through regulating cell proliferation, especially lung myofibroblasts, by an intracrine pathway. The fundamental knowledge obtained from this study will help understanding pathogenic mechanisms of neonatal lung disease such as bronchopulmonary dysplasia, and may also provide clues for designing novel therapeutic strategies.
|Commitee:||Snead, Malcolm, Warburton, David|
|School:||University of Southern California|
|School Location:||United States -- California|
|Source:||MAI 47/06M, Masters Abstracts International|
|Subjects:||Biology, Health sciences|
|Keywords:||BDP, Chronic lung disease, Development, Lung, Neonatal, Parathyroid hormone-related protein|
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