The long term goal of this proposal is to gain a better understanding of the mechanisms responsible for increased collagen accumulation in the lung. Injury to either the alveolar epithelium or capillary endothelium leads to a complex interaction of inflammatory cells and effector molecules. Interstitial fibroblasts are activated during this process leading to production of large amounts of extracellular matrix material, including type I and type III collagen. The effect of several inflammatory factors on fibroblast collagen production have been examined in our laboratories. Our data and that of others indicate that transforming growth factor beta (TGF-beta) stimulates fibroblasts to produce significant amounts of collagen. In addition, our results demonstrate that TGF-beta stimulates lung fibroblasts to increase collagen production without increasing proliferation. Steady state mRNA levels of alpha 1(I) and alpha I(III) collagen chains increase during stimulation with TGF-beta. The increase in alpha 2(I) mRNA steady state levels varied depending on cell type. There was no increase in alpha 2(I) mRNA when human lung fibroblasts were stimulated with TGF-beta. In the case of TGF-beta, collagen may be stimulated by increased by a transcriptional and/or a post-transcriptional mechanism.
The specific aims of this proposal are to 1) determine the effects of TGF-beta on lung fibroblast expression of collagen type I and type III genes by examining the abundance, transcription, and stability of collagen mRNA, 2) identify and characterize the cis acting regulatory or stabilizing elements of the collagen type I genes, 3) identify and compare DNA binding proteins, in TGF-beta stimulated versus unstimulated fibroblast, and 4) determine whether the regulation of collagen accumlation is altered in fibroblasts derived from bleomycin-treated rat lungs.
| Ritzenthaler, J D; Goldstein, R H; Fine, A et al. (1993) Regulation of the alpha 1(I) collagen promoter via a transforming growth factor-beta activation element. J Biol Chem 268:13625-31 |
| Guenette, D K; Ritzenthaler, J D; Foley, J et al. (1992) DNA methylation inhibits transcription of procollagen alpha 2(I) promoters. Biochem J 283 ( Pt 3):699-703 |
| Ritzenthaler, J D; Goldstein, R H; Fine, A et al. (1991) Transforming-growth-factor-beta activation elements in the distal promoter regions of the rat alpha 1 type I collagen gene. Biochem J 280 ( Pt 1):157-62 |
