The pathobiology of fibrotic lung disease includes a dynamic interplay among several biological processes that regulate fibroblast population size and position. Studies in patients with fibrotic lung disease have permitted pathophysiological inferences to be made about which processes and which regulatory molecules might be involved in the fibroproliferative response. Animal model systems have been useful in further refining these inferences. Such models, however, have proved less tractable in pinpointing the precise processes and regulatory molecules that are essential for the genesis of the anatomic changes observed in fibrotic lung disease. We propose to examine one question essential to understanding the genesis of the fibroproliferative response: Can excess concentrations of a ligand promoting fibroblast migration and proliferation within the alveolar microenvironment lead to pulmonary fibrosis, or must the alveolar wall be injured before fibrosis can be manifested? To answer this question we have chosen to utilize a transgenic murine model in which lung type 2 epithelial cells express PDGF B under the direction of surfactant protein C DNA regulatory elements. Our proposal has 2 Specific Aims: Specific Aim 1. Generate transgenic mice bearing a chimeric gene consisting of 5' flanking sequences from the human surfactant protein C (SP-C) gene and human PDGF B coding sequences. Our objective is to genetically program the type 2 alveolar epithelial cells of these mice to secrete biologically active, homodimeric PDGF B. Specific Aim 2. Determine if increased concentrations of homodimeric PDGF B in the alveolar microenvironment by itself is sufficient to induce fibrosis, or whether injury to the alveolar wall must occur for fibrosis to develop. Therapeutic strategies hinge critically on determining whether injury to the alveolar wall must be prevented or whether we can focus primarily on interdiction of profibrotic ligands. Our goal is to provide experimental evidence to guide in developing therapies for a lethal class of disorders that remain largely refractory to current treatment options.