Interstitial lung fibrosis (ILF) remains a highly lethal disease with a prognosis similar to that of lung cancer. ILF may result from a wide range of processes of known and unknown origin. Although a variety of compounds have been proven to possess antifibrotic effects in animal models of lung fibrosis, their long-term effectiveness in clinical situations have been questionable due to the possibility of development of systemic toxicity. The finding that dietary supplementation with taurine and niacin consistently, offers a marked protection against bleomycin (BL)-induced ILF in rodent models has opened a potentially novel therapeutic approach for the management of this crippling disease. The major objectives of this proposal in a three-dose BL-hamster model of lung fibrosis are: 1) evaluate the therapeutic potential of taurine and/or niacin as antifibrotic agents, once the fibrotic process has already started; 2) evaluate the role of taurine and/or niacin in epithelial cell repair via increasing the intracellular concentrations of NAD+ and ATP; 3) evaluate the ability of taurine and/or niacin to modulate the synthesis of TGF-BETA at the gene expression level and its subsequent production; 4) evaluate the ability of taurine and/or niacin to suppress the lung collagen reactivity at the gene expression level of procollagens, prolylhydroxylase, lysyloxidase and collagenase; and 5) evaluate the direct effects of taurine and/or niacin on toxicity and functions of lung fibroblasts grown in culture. A multidisciplinary approach which integrates the tools of biochemistry, molecular biology, morphometry and immunocytochemistry as described in this project will not only uncover the molecular basis for the antifibrotic effects of taurine and/or niacin in vivo, it will also unravel the cellular mechanisms important in the pathogenesis of lung fibrosis.
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