Dissecting macrophage regulation of lung epithelial regeneration

Lungs are continually exposed to infections and toxins, which frequently damage the internal lining of the lungs, the epithelium. Widespread epithelial damage compromises lung function and occurs in fatal lung injury, including COVID-19 lung disease. It is therefore vital that the lung can regenerate and repair itself to ensure optimum functioning and protect against infections. But the regeneration process is very poorly understood and functions abnormally in several human lung conditions. No existing treatments promote lung regeneration. Understanding the process of how the lung naturally regenerates after injury may help develop new treatments that promote lung regeneration after serious infection or damage.

It is known that following lung injury, cells from the body's immune system called macrophages increase in numbers and are critical to accelerate healing. But what sort of macrophage promotes epithelial regeneration and how they achieve this is not clear. This study will investigate which macrophages promote lung epithelial regeneration (focusing on 'interstitial macrophages'), how the numbers of these macrophages are increased after lung injury, and the methods these macrophages use to coordinate regeneration of the lung.

This research will be achieved by laboratory-based investigation and involve using immune cells and epithelial cells isolated from human lungs and using models of lung injury and repair. The research will be carried out primarily by Dr Christopher Lucas, a consultant in respiratory medicine and researcher based at the University of Edinburgh. This work will be performed mainly at the newly formed Institute for Regeneration and Repair, the world's largest institute dedicated to tissue regeneration. The work will be supported by scientists at the University of Edinburgh, including Dr Jenkins, Dr Bain, Dr Gray and Prof. Walmsley who are world experts in macrophages and lung inflammation. Part of the work will also be delivered by national and international collaborations with the Carlin group at the Beatson UK, and the Perry Laboratory at Sloan Kettering in New York, USA, to benefit from those team's expertise in analysing immune cell responses.

By using this unique combination of scientists, resources and novel research ideas we aim to identify new mechanisms of lung regeneration to help develop new treatments that will promote lung regeneration after serious infection or damage.

In the lung the epithelium is the interface between the external environment and the host, making injury frequent, often severe, and with high mortality and morbidity. Effective epithelial regeneration is therefore critical to restore organ function, prevent pathogen invasion and prevent mortality. But several pulmonary diseases are typified by epithelial injury and aberrant regeneration, and no treatments currently target pulmonary regeneration. Epithelial regeneration is therefore a bona fide therapeutic target and unmet need in lung injury.

Following epithelial injury, it is unclear what microenvironmental cues support a regeneration-permissive environment. While many factors may drive epithelial regeneration, I have found that lung injury expands interstitial macrophages which critically regulate epithelial proliferation and regeneration. However, the specific macrophage population(s) and molecules promoting regeneration remain largely unexplored. I hypothesise that crosstalk between interstitial macrophages and their environment critically regulates epithelial regeneration and understanding these mechanisms will identify therapeutic targets to promote lung regeneration in humans.

I will utilise advanced methodology to perform fundamental discovery science (lung epithelial culture, RNA-sequencing and proteomics, tissue-specific transgenic animals and models of lung injury and regeneration). My aims are to:
1. Determine phenotype and function of macrophages promoting lung regeneration.
2. Define TLR9-driven interstitial macrophage regulation and impacts on regeneration.
3. Resolve mechanisms of macrophage-epithelial crosstalk that enhance regeneration.

By defining these mechanisms, I will identify targets that boost lung regeneration. My long term aim is to use this knowledge to develop new therapeutic approaches that overcome otherwise untreatable and unsurvivable severe lung injury in humans.