Excess accumulation of type I collagen is key feature of the fibrosing lung diseases, causing disruption of normal pulmonary function. This increase in type I collagen likely results from a complex interplay of effector substances which activate or inhibit collagen formation by lung fibroblasts. We have a long-standing interest in the mechanisms whereby key regulatory molecules such as transforming growth factor-beat(TGF- beta), prostaglandin E2 (PGE2), and retinoic acid (RA) affect type I collagen accumulation. We believe that the examination of interactions between these mediators will suggest possible strategies for modulating type I collagen accumulation in the lung. TGF-beta activates transcription via signals transmitted by two signalling receptors (type I and type II), each containing cytoplasmic serine-threonine kinase domains. We found that TGF-beta stimulates and PGE2 inhibits type I receptor mRNA levels. These findings may explain, in part, the sustained elevation of type I collagen formation induced by TGF-beta and the selective inhibition of TGF-beta action on lung fibroblasts by PGE2. We have cloned the type I TGF-beta receptor promoter. In the first part of this proposal, we will employ the human type I receptor promoter to identify the genetic mechanisms whereby TGF-beta and PGE2 regulate type I receptor promoter activity. Subsequently, by over-expressing a kinase deficient or a wild- type I receptor cDNA, we will characterize the precise relation between type I receptor expression and alpha 1(I) promoter activity. Using an alpha 1(I) collagen promoter construct, we plan to identify the cis-acting elements and trans-acting factors which mediate the decrease in type I collagen gene transcription by PGE2 and RA. We hypothesize that the inhibitory effect of PGE2 on type I collagen formation and TGF-beta type I receptor expression indicates that misoprostol, a PGE1 analog, may have therapeutic value in pulmonary fibrosis. Notably, we found that misoprostol inhibited basal and TGF-beta-induced collagen formation by lung fibroblasts in vitro. Thus, as the final part of this proposal we will determine the effect of prednisone with or without immunotherapy, or misoprostol on collagen biosynthesis in patients with fibrosing lung diseases. We will assess collagen biosynthesis by measuring pro-collagen peptides, lysyl oxidase activity, and collagen metabolites. Overall, the studies outlined in this component of the SCOR proposal will provide key information regarding the modulation of type I collagen accumulation in pulmonary fibrosis.
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