A novel in vivo Drosophila model of chronic inflammatory lung disease for non-invasive live imaging and mechanistic analyses

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is a major global health problem with rising incidence. It is a complex, polygenic disease with multiple environmental risk factors and systemic effects. Mechanistic understanding of COPD thus requires tractable models
that capture disease complexity. In vivo research into chronic inflammatory lung diseases is primarily performed in mammals. There is a clear need for more experimentally tractable models that enable non-invasive imaging of dynamic cellular interactions and large-scale genetic or pharmacological screens. This NC3Rs-supported project aims to establish a novel in vivo model of cigarette smoke (CS)-induced COPD using the invertebrate Drosophila.
Methods: We have explored the dynamic interactions between damaged airway epithelia and inflammation through live imaging, using the optically translucent pupal stage of Drosophila. Proteomic analyses, in vivo imaging, and molecular assays (e.g. RT-qPCR and ELISA) have provided in-depth insight into airway-specific, immune-specific, and whole organism responses to CS.
Results: Harnessing Drosophila’s unrivalled experimental tractability, we show Drosophila airways and immune cells develop key COPD-like phenotypes, including increased inflammation (with upregulation of Drosophila IL-6 signalling), elevated oxidative stress and hypoxia, and reduced survival following CS exposure. Drosophila also display delayed development following chronic CS exposure at the pupal stage. At the proteome level, CS-exposed Drosophila airways exhibit significant changes in orthologues of up to 73% of proteins changed in human COPD.
Conclusions: Use of Drosophila may not only reduce the reliance on less tractable vertebrate models, but could also offer a valuable model of CS exposure from adolescence, the most common risk factor for COPD. We envision Drosophila represents a rapid, cost-effective model to expand the toolkit available to COPD researchers and will enable large-scale screens to test innovative therapeutic strategies.

Date of Award	30 Sept 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	David N Sheppard (Supervisor), Helen M A Weavers (Supervisor) & Paul B Martin (Supervisor)