Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.

Pulmonary fibrosis comprises a group of interstitial disorders of the lung parenchyma that develop as a consequence of multiple causes, including radiotherapy and chemotherapy for lung neoplasms (1, 2). The pathophysiologic events induced by radiation have striking similarities to those that occur after other types of lung injury, such as surgery, chemotherapy, and idiopathic pulmonary fibrosis (IPF; reference 3). IPF is the most common form of lung fibrosis with a prevalence of 16–18 cases per 100,000 (4, 5). Clinically, IPF is characterized by interstitial infiltrates, progressive dyspnea, and worsening of pulmonary function that may lead to death from respiratory failure (1, 6, 7). Despite the medical need, there has been remarkably little progress in the development of effective therapeutic strategies (1, 6–9). It has been proposed that fibrogenesis is not a unique pathologic process but rather, is due to an excess of the same biologic events involved in normal tissue repair (10). Persistent and exaggerated wound healing ultimately