Alveolar macrophages have been implicated in the pathogenesis of a number of acute and chronic lung disorders. A characteristic feature of many of the chronic lung disorders is that the types of macrophages in the lung have become more monocyte-like. There are differences in function when alveolar macrophages from normal lung are compared to macrophages from patients with chronic lung disorders, including increased cytokine and growth factor release. My mentor's laboratory recently found that normal human alveolar macrophages, compared to monocytes, have a decreased capacity to express PKC- induced DNA-binding activity of the transcription factor, AP-1. The preliminary data suggest that the defect in AP-1 DNA binding is due to a defect in redox regulation of the AP-1 proteins by the nuclear protein Ref-1. This observation formed the basis for this proposal and suggests one reason why the function of normal alveolar macrophages might differ from monocytes, or the monocyte-like macrophages of various lung diseases. The overall hypothesis of these studies is that there are differences in expression of the DNA-binding activity of AP-1 by normal alveolar macrophages compared to monocytes or monocyte-like macrophages in the lungs of patients with chronic lung disorders. I will pursue these hypotheses with the following specific aims: 1) determine if there are Ref-1-induced differences in DNA binding activity of AP-1 in normal alveolar macrophages compared to monocytes. 2) determine if the lack of alveolar macrophage AP-1 binding has biological consequences. 3) determine whether stimuli that are associated with the development of chronic lung disease alter expression of Ref-1 and AP-1 binding. 4) determine if prototype mediators that are relevant to chronic lung disorders alter the AP-1 DNA binding activity of alveolar macrophages compared to monocytes. 5) determine if there are differences in AP-1 DNA binding activity in alveolar macrophages from the lungs of patients with chronic lung disorders, compared to alveolar macrophages from normal lungs. The studies are important because the shift in phenotype of macrophages in the lung may be critical to the pathogenesis of a number of chronic lung disorders.
| Flaherty, Dawn M; Monick, Martha M; Hinde, Sara L (2006) Human alveolar macrophages are deficient in PTEN. The role of endogenous oxidants. J Biol Chem 281:5058-64 |
| Flaherty, Dawn M; Hinde, Sara L; Monick, Martha M et al. (2004) Adenovirus vectors activate survival pathways in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 287:L393-401 |
