Single cell RNA sequencing reveals novel inflammatory mechanisms of human acute respiratory distress syndrome

Abstract

Abstract The acute respiratory distress syndrome (ARDS) is a common etiology of acute respiratory failure that results from overwhelming pulmonary inflammation. Since prior bulk RNA sequence analyses have provided limited insights into ARDS pathogenesis, we used the approach of single cell RNA sequencing (scRNA-seq) to probe ARDS at a higher resolution. Towards this end, scRNA-seq data of peripheral blood mononuclear cells (PBMCs) of patients with pneumonia and sepsis with early ARDS were compared to that of sepsis patients who did not develop ARDS. We detected a previously unrecognized reduced frequency of NK cells in the PBMCs of ARDS patients, which also showed complete loss of IFNGR1 expression. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison to monocytes from patients without ARDS. This included a pro-inflammatory signature with up-regulation of multiple type I IFN-induced genes, especially in CD16+ cells. To generate an ARDS risk score, we identified 29 differentially expressed genes in the monocytes of these patients, 17 of which showed a similar profile in cells of patients in independent cohorts. Genes with increased expression in monocytes that may have relevance in ARDS pathogenesis include RAB11A, known to inhibit neutrophil efferocytosis, ATP2B1, a calcium pump that exports Ca2+ implicated in endothelial barrier disruption, and SPARC, associated with processing of pro-collagen to collagen. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.