G-CSF and STAT3 link inflammation to alveolar epithelial regeneration

项目总结

Project Summary The acute respiratory distress syndrome (ARDS) is a diffuse inflammatory lung disease that has been associated with multiple direct and indirect pulmonary insults. In ARDS, these diverse etiologies share a common histologic pattern known as diffuse alveolar damage in which the alveolar cells are damaged and the alveoli themselves become filled with proteinaceous fluid. As a result, oxygenation is severely impaired. Despite advances in clinical care, mortality remains high and the development of ARDS pharmacotherapy remains a major unmet medical need. Historically, research has focused on the inflammatory processes that underlie ARDS. This led to several clinical trials of anti-inflammatory medications such as corticosteroids and non-steroidal anti-inflammatory drugs. This strategy sought to limit tissue damage but did not promote restoration of normal lung architecture per se. To date, no anti-inflammatory medication has shown a convincing mortality benefit in ARDS. In this proposal we postulate that one reason anti-inflammatory medications have not shown a convincing benefit may be because the inflammatory cells themselves promote the restoration of normal lung architecture following ARDS. In fact, preliminary data show a link between the inflammatory response and subsequent re- epithelialization. This project will enhance our insight into reparative mechanisms in the lung and bolster a therapeutic strategy that seeks to directly promote restoration of the alveolar epithelium as a treatment for ARDS. The scientific objective of this proposal is to determine how granulocyte-colony stimulating factor (G-CSF), a key regulator of neutrophil homeostasis, promotes alveolar regeneration in a murine model of acid-induced lung injury, which is similar to human ARDS. Preliminary data suggest that these mice recruit fewer neutrophils to the alveoli following lung injury and also demonstrate significantly impaired alveolar repair three days after acid aspiration. The aims of this proposal are thus 1) Elucidate the mechanisms of G-CSF production and understand how it stimulates type II pneumocytes, a key reservoir of progenitor type I pneumocytes, to repair the alveolar epithelium following acute lung injury. 2) Determine the contribution of STAT3 activation in AT2 cells, mediated by G-CSF, to alveolar epithelial regeneration. This proposal's other key objective is to train the candidate in the nascent field of pulmonary epithelial regeneration. This proposal outlines an individualized plan of mentoring, didactic coursework and professional development to help the candidate become a leader in understanding how innate inflammatory responses influence the repair mechanisms in the lung following ARDS.