Coordinated regeneration of lung epithelial and endothelial compartments

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Influenza alone kills as many as 500,000 people annually, and at least 4.5 million have died from SARS-CoV-2 during this ongoing pandemic, with mortality from both respiratory viruses largely due to viral pneumonia progressing to acute respiratory distress syndrome (ARDS). Significant focus has been placed on regeneration of the epithelium after influenza, but relatively little is known as to how the endothelium is repaired, a critical question since vascular endothelial integrity is necessary to prevent ARDS-associated pulmonary edema, hypoxemia, and mortality. We recently demonstrated that at least 20% of the lung's vascular endothelium is regenerated by 1 month after infection, indicating a robust capacity for endothelial repair. We therefore investigated signaling pathways which might modulate this regenerative functionality. Somewhat unexpectedly given its role in promoting fibrosis, we observed that endothelial- specific blockade of TGF-β signaling prevents effective repair of the lung endothelium and results in inefficient physiologic recovery. Moreover, in order to achieve coordinated, functional tissue repair, we reasoned that lung endothelial cells might influence repair of the adjacent epithelium by release of angiocrine factors. In keeping with this notion, we identified a matricellular protein, SPARCL1, which is secreted by injury-activated endothelial cells and serves to enhance alveolar epithelial regeneration, at least in part by modulating TGF-β. Based on our cumulative findings, we hypothesize that injury-activated endothelial cells engage a TGF-β / SPARCL1 axis to coordinately regulate lung endothelial and epithelial repair. The major objectives to address this hypothesis are 1) mechanistically define how TGF-β promotes lung vascular repair and 2) determine whether and how SPARCL1 acts as an angiocrine factor to promote alveolar epithelial regeneration. Successful completion of these studies will inform approaches designed to enhance endothelial cell regenerative potential and promote effective lung repair / prevent mortality in ARDS and viral pneumonia.