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Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome.

ABSTRACT: Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients without ARDS, including downregulation of SOCS3 expression, accompanied by a proinflammatory signature with upregulation of multiple type I IFN-induced genes, especially in CD16+ cells. To generate an ARDS risk score, we identified upregulation of 29 genes in the monocytes of these patients, and 17 showed a similar profile in cells of patients in independent cohorts. Monocytes had increased expression of RAB11A, known to inhibit neutrophil efferocytosis; ATP2B1, a calcium pump that exports Ca2+ implicated in endothelial barrier disruption; and SPARC, associated with processing of procollagen to collagen. These data show that monocytes of ARDS patients upregulate expression of genes not just restricted to those associated with inflammation. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC7406263 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome.

Jiang Yale Y Rosborough Brian R BR Chen Jie J Das Sudipta S Kitsios Georgios D GD McVerry Bryan J BJ Mallampalli Rama K RK Lee Janet S JS Ray Anuradha A Chen Wei W Ray Prabir P

JCI insight 20200709 13

Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients ...[more]

PMID: 32554932

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Project description:BACKGROUND:The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear. METHODS:We randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ?8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days. RESULTS:The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P?=?0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months. CONCLUSIONS:Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).

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Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome.

Publications

Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome.

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