Are circulating endothelial cells the next target for transcriptome-level pathway analysis in ARDS?

Acute respiratory distress syndrome (ARDS) has had no mortality-improving pharmacological intervention despite 50 years of high-caliber research due to its heterogeneity (Huppert LA, Matthay MA, Ware LB. Semin Respir Crit Care Med 40: 31-39, 2019). For the field to advance, better definitions for ARDS subgroups that more uniformly respond to therapies are needed (Bos LDJ, Scicluna BP, Ong DSY, Cremer O, van der Poll T, Schultz MJ. Am J Respir Crit Care Med 200: 42-50, 2019; Dickson RP, Schultz MJ, T van der P, Schouten LR, Falkowski NR, Luth JE, Sjoding MW, Brown CA, Chanderraj R, Huffnagle GB, Bos LDJ, Biomarker Analysis in Septic ICU Patients (BASIC) Consortium. Am J Respir Crit Care Med 201: 555-563, 2020; Sinha P, Calfee CS. Am J Respir Crit Care Med 200: 4-6, 2019; Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, NHLBI ARDS Network. Lancet Respir Med 2: 611-620, 2014; Hendrickson CM, Matthay MA. Pulm Circ 8: 1-12, 2018). A plethora of high-quality clinical research has uncovered the next generation of soluble biomarkers that provide the predictive enrichment necessary for trial recruitment; however, plasma-soluble markers do not specify the damaged organ of origin nor do they provide insight into disease mechanisms. In this perspective, we make the case for querying the transcriptome of circulating endothelial cells (CECs), which when shed from vessels after inflammatory insult, become heralds of site-specific inflammatory damage. We review the application of CEC quantification to multiple disease phenotypes (including myocardial infarction, vasculitides, cancer, and ARDS), in each case supporting the association of CEC number with disease severity. We also argue for the utility of single-cell RNA transcriptomics to the understanding of cell-specific contributions to disease pathophysiology and its potential to uncover novel insight on signals contributing to CEC shedding in ARDS.