This is a multidisciplinary program involving biochemistry, cell biology, medicine and pathology that is oriented toward lung cell biology and lung biochemistry. The focal points are the interstitium of the lung parenchyma, surfactant,and the smooth muscle and extracellular matrix of pulmonary blood vessels. The theme of the project is that extracellular matrix has a vital role in normal lung development and maintenance of normal lung structure and that disturbances in synthesis, turnover and distribution of matrix are central to diseases of lung structure such as pulmonary emphysema, idiopathic pulmonary fibrosis and various forms of chronic pulmonary hypertension. The program will address expression of lung fibroblast phenotype, regulation of production of extracellular matrix, mechanisms and consequences of turnover of lung extracellular matrix, and the biochemistry of protein associated with surfactant. The following molecules will be emphasized: fibronectin, the fibronectin receptor, surfactant- associated collagenous proteins, elastin, human neutrophil elastase, type IV collagen, human interstitial collagenase, human tissue inhibitor of metalloproteinases (TIMP) and a newly discovered elastogenic factor released by pulmonary artery smooth muscle cells. Experimental models will be used to examine the role of matrix molecules in lung development, mechanisms of fibroblast migration into plasma clot, the effects of human interstitial collagenase upon lung, the effects upon inflammatory cells of peptides released from lung basement membrane, alterations in pulmonary artery matrix in pulmonary hypertension induced by alveolar hypoxia, and the regulation of collagenase production by inflammatory cells and isolated structure cells of the lung. Human studies will utilize lung biopsy material, cells and fluid obtained by bronchoalveolar lavage, plasma and circulating inflammatory cells. The investigative approaches will include cell culture, a variety of protein chemistry techniques, immunoassys, immunolocalization at the light and EM levels, determination of mRNA levels by quantitative assay and by 'in sit' hybridization, and radiocarbon dating to determine rates of human lung elastin turnover. Core facilities will be develop polyclonal and monoclonal antibodies assist with immunological procedures, will be used to develop polyclonal and monoclonal antibodies, assist with immunological procedures, and perform histological analyses that will utilize immunological reagents and molecular probes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (SRC (SS))
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Barnes-Jewish Hospital
Saint Louis
United States
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Byers, Derek E; Wu, Kangyun; Dang-Vu, Geoffrey et al. (2018) Triggering Receptor Expressed on Myeloid Cells-2 Expression Tracks With M2-Like Macrophage Activity and Disease Severity in COPD. Chest 153:77-86
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Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98
Holtzman, Michael J; Byers, Derek E; Brett, Jennifer-Alexander et al. (2014) Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S287-91
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Gharib, Sina A; Altemeier, William A; Van Winkle, Laura S et al. (2013) Matrix metalloproteinase-7 coordinates airway epithelial injury response and differentiation of ciliated cells. Am J Respir Cell Mol Biol 48:390-6
Pressly, Eric D; Pierce, Richard A; Connal, Luke A et al. (2013) Nanoparticle PET/CT imaging of natriuretic peptide clearance receptor in prostate cancer. Bioconjug Chem 24:196-204

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