Pathogenic airway macrophage adaptation in the chronically inflamed lung

Severe lung inflammation has consequences long after it has resolved, but the underlying mechanisms are unknown. Asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and post-viral patients all experience recurrent infections that exacerbate the disease, and this accounts for the majority of hospitalisations and associated healthcare costs. Airway macrophages play an important undisputed role in respiratory tract immunity, but their adaptation by the altered microenvironment in human lung disease is unexplored. We will define phenotypic, functional and transcriptomic boundaries between airway macrophages extracted from the healthy airspaces and their adaptation by cigarette smoke and in the development of chronic lung disease. Our goal is to restore critical pathways that maintain immune health. We will: 1. Develop further the pathways that underpin pathogenic adaptation of airway macrophages in COPD. 2. Unravel airway macrophage heterogeneity in health and COPD by the unbiased approach of single cell sequencing. 3. Facilitate sub-population plasticity by delivery of nanoparticles containing nucleic acid payloads that reverse adaptation. 4. Define the functional outcome of altering airway macrophages via nanoparticle delivery in vivo.