ABSTRACT Fibroproliferative illnesses leading to organ fibrosis and failure are responsible for approximately 45% of deaths in developed countries. Whether idiopathic, triggered by environmental factors, infections, or genetics, organ fibrosis results in significant morbidity and mortality. Organ fibrosis is responsible for health care costs exceeding $10 billion/year. It is estimated that the number of deaths due to fibrosis is double the number of deaths due to cancer, and that organ fibrosis results in significant physical, emotional, and financial burdens. Specifically, lung fibrosis can be idiopathic, associated with connective tissue diseases such as systemic sclerosis (SSc), or triggered by environmental and occupational exposures such as radiotherapy. Lung involvement is currently the leading cause of death of patients with SSc. There are currently no effective therapies to treat existing lung fibrosis as recently approved drugs merely reduce disease progression and result in significant side effects. Thus, the only curative option for patients is organ transplantation, which is impossible at the scale needed. We have identified a peptide derived from collagen XVIII which exerts anti-fibrotic effects in murine and human pre- clinical models of lung fibrosis. The beneficial effects include reducing fibrosis in lung tissues of patients with pulmonary fibrosis who underwent lung transplantation and thus have end-stage severe fibrosis, an effect not seen with other drugs that are approved or being evaluated for these illnesses. We propose to assess the therapeutic potential of the peptide in vivo in a murine model of lung fibrosis. We also propose to identify the minimal effective dose and optimal dosing frequency and conduct pilot toxicity, pharmacokinetic, and biodistribution analyses. Successful completion of this project will support our long-term goal of translating our findings to the clinic and providing patients with pulmonary fibrosis with an effective therapy. Identifying a peptide effective at reducing fibrosis represents a critical unmet need. Our approach is also likely to have broad impact and relevance for fibrosis in different organs.