The overall objective of the proposed study is to define an efficacious antifibrotic drug which can be therapeutically used to prevent and/or reverse the interstitial pulmonary fibrosis (IPF) seen in humans. IPF is a crippling and potentially lethal disease which may result from a wide range of processes of known and unknown origins. A variety of compounds has been tested in the past for their antifibrotic potential in the animal model of lung fibrosis, but their therapeutic desirability has been severely limited due to systemic toxicity following long term treatment. The knowledge that the pharmacological intervention for inhibition of collagen synthesis and accumulation can be successfully targeted at the transcriptional level as demonstrated by treatment with interferons (INFs) and their inducers, opens the feasibility of a novel therapeutic approach for the management of IPF. Therefore, the specific aims of the proposed study are: 1) to evaluate the antifibrotic potential of alpha, beta and gamma INFs and their inducers in the bleomycin-rodent model of lung fibrosis; 2) to investigate whether or not INF inducers exert their antifibrotic effect by inducing INFs in serum and lung, as documented, either by measuring the INF levels by an in vitro antiviral assay or by measuring the activities of two INF-mediated enzymes (2-5A synthetase and kinase-P67K); 3) to investigate whether or not the antifibrotic effect of INFs and their inducers resides in their ability to suppress the bleomycin-induced increases in mRNAs responsible for the synthesis of Type I and Type III procollagens in the lung; 4) to investigate whether or not the antifibrotic effect of INFs and their inducers is associated with an alteration in the hemoprotein metabolism of lung; and 5) to assess the direct effects of INFs and their inducers on the functionality of cultured lung fibroblasts with respect to growth, collagen synthesis at the gene expression level, secretion and degradation. A multidisciplinary approach, as proposed in this project will not only explore the feasibility of a novel therapeutic approach to lung fibrosis in vivo but it will also unravel the cellular mechanisms important in the pathogenesis of fibrotic processes. If the adverse side effects of INFs and INF-inducers prove to be acceptable, they might be useful in the therapy of fibrotic diseases including IPF.
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