Project 462755

The efficient uptake of oxygen by the lung is dependent on maintaining a thin but highly efficient barrier between the air spaces and the blood. This barrier is comprised of a thin layer of endothelial cells (the inner lining of blood vessels) and epithelial cells (cells that line the airways). Viral (i.e., COVID-19 or influenza) or bacterial infection can damage this fragile barrier, resulting in flooding of the air sacs and severe inflammation, preventing oxygen from reaching the blood. This is called acute respiratory distress syndrome (or ARDS) and these critically ill patients often require mechanical ventilation and have high death rates. We have shown that selective damage to the lung endothelial cells reproduces many of the characteristics of ARDS. However, we have also shown that the lung has an amazing capacity to regenerate and repair blood vessels and recover its ability to exchange oxygen. Using new technologies that allow us to look at which genes are active in each individual cell of the entire lung (single-cell transcriptomics), we have identified novel stem- and progenitor-like endothelial cell populations that orchestrate the regeneration of damaged endothelial cells and the repair of the small blood vessels that surround the air sacs, thereby allowing the lung to recover its ability to provide oxygen to the body efficiently. We will study the relevance of these novel stem and progenitor populations for resolution of severe lung injury in clinically relevant animal models of ARDS with particular attention to the influence of biological sex (male or female) and advancing age, which are known risk factors for poor outcomes in this disease. We will also develop and test novel therapies designed to enhance lung endothelial cell regeneration and small blood vessel repair in preclinical models of ARDS, which may provide new tools that can improve survival of critically ill patients such as those with COVID-19.