and Specific Aims.) Interstitial pulmonary fibrosis is characterized by alterations in the lung parenchyma with increased fibroblast numbers, excess connective tissue and increased rate of matrix synthesis. The mechanisms responsible for these tissue alterations are poorly understood. Fibroblasts are the major cell type responsible for normal connective tissue turnover and accumulation of matrix elements in fibrosis. Cytokines, growth factors, complement proteins and other inflammatory mediators have been implicated in the pathogenesis of fibrosis in man. Evidence indicates that human lung fibroblasts are heterogeneous and subpopulations interact differently with inflammatory mediators. The application proposes to utilize antibodies and cDNAs for the two C1q receptors to identify fibroblast subpopulations in normal adult and fibrotic human lungs.
The Specific Aims are: 1) to produce antibodies against human lung fibroblast receptors for collagen- and globular- domains of the C1q molecule and determine their specificity to human lung fibroblast subpopulations; 2) to isolate from human lung fibroblasts cDNAs coding for the receptors for collagen- and globular-domains of C1q molecule and assess differential expression of these receptors in two human lung fibroblast subpopulations; 3) to study the regulation of C1q receptors by cytokines in human lung fibroblasts and determine whether synthesis of these receptors is related to type I collagen gene expression; 4) to identify fibroblast subpopulations with differential C1q receptors and collagen synthesis in normal and fibrotic human lungs using antibodies and cDNA probes. From these experiments, the role of fibroblasts with different C1q receptors and the role of fibroblast heterogeneity in idiopathic pulmonary fibrosis (IPF) may be determined. The results may also help to identify potential marker(s) for early detection of fibrosis and may aid in interventional studies.
|Lurton, J; Soto, H; Narayanan, A S et al. (1999) Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha. Exp Lung Res 25:151-64|
|Narayanan, A S; Lurton, J; Raghu, G (1997) Distribution of receptors of collagen and globular domains of C1q in human lung fibroblasts. Am J Respir Cell Mol Biol 17:84-90|
|Pitaru, S; McCulloch, C A; Narayanan, S A (1994) Cellular origins and differentiation control mechanisms during periodontal development and wound healing. J Periodontal Res 29:81-94|
|Idell, S; Kumar, A; Zwieb, C et al. (1994) Effects of TGF-beta and TNF-alpha on procoagulant and fibrinolytic pathways of human tracheal epithelial cells. Am J Physiol 267:L693-703|
|Idell, S; Zwieb, C; Boggaram, J et al. (1992) Mechanisms of fibrin formation and lysis by human lung fibroblasts: influence of TGF-beta and TNF-alpha. Am J Physiol 263:L487-94|
|Akamine, A; Raghu, G; Narayanan, A S (1992) Human lung fibroblast subpopulations with different C1q binding and functional properties. Am J Respir Cell Mol Biol 6:382-9|
|Pardo, A; Selman, M; Ramirez, R et al. (1992) Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lungs. Chest 102:1085-9|
|Siminski, J T; Kavanagh, T J; Chi, E et al. (1992) Long-term maintenance of mature pulmonary parenchyma cultured in serum-free conditions. Am J Physiol 262:L105-10|
|Narayanan, A S; Whithey, J; Souza, A et al. (1992) Effect of gamma-interferon on collagen synthesis by normal and fibrotic human lung fibroblasts. Chest 101:1326-31|
|Raghu, G; Masta, S; Meyers, D et al. (1989) Collagen synthesis by normal and fibrotic human lung fibroblasts and the effect of transforming growth factor-beta. Am Rev Respir Dis 140:95-100|