Defining the role of lung macrophage metabolism during lung fibrosis

Tissue wound healing is a normal consequence of injury but if dysregulated, can lead to pathology, as seen in idiopathic pulmonary fibrosis (IPF). IPF is a chronic debilitating lung disease with no cure, characterized by deposition of excessive extracellular matrix in the lung parenchyma. Macrophages are key components of lung defence with central roles in resolution of inflammation and repair. My published and preliminary work indicates that pulmonary macrophages are metabolically rewired during fibrosis and furthermore, that these metabolic phenotypes are related to disease severity. I hypothesise that metabolic alterations underlie pulmonary macrophage profibrotic phenotypes and that targeting macrophage metabolism is a tractable therapeutic strategy. This project aims to answer the following key questions (Figure 1A); - What are the metabolic phenotype and nutrient dependencies of macrophage subsets in the fibrotic lung? - How does macrophage metabolism influence stromal phenotypes in the fibrotic lung? - Can targeting lipid metabolism in macrophages ameliorate lung fibrosis? Using innovative tools and therapeutics I will define the role of lung macrophage metabolism using robust animal models, primary human cells, and unique clinical cohorts. Together, these studies will delineate the pathways that define balance between health and disease, revealing novel approaches for therapeutic intervention.