Alveolar Macrophage Transcriptional Programs Are Associated with Outcomes in Acute Respiratory Distress Syndrome

Abstract

Rationale: Serial measurements of alveolar macrophage (AM) transcriptional changes in patients with acute respiratory distress syndrome (ARDS) could identify cell-specific biologic programs that are associated with clinical outcomes. Objectives: Determine whether AM transcriptional programs are associated with prolonged mechanical ventilation and 28-day mortality in subjects with ARDS. Methods: We performed genome-wide transcriptional profiling of AMs purified from bronchoalveolar lavage fluid collected from 35 patients with ARDS. Cells were obtained at baseline (Day 1), Day 4, and Day 8 after ARDS onset (n = 68 total samples). We identified biologic pathways that were enriched at each timepoint in subjects alive and extubated within 28 days after ARDS onset (Alive/ExtubatedDay28) versus those dead or persistently supported on mechanical ventilation at day 28 (Dead/IntubatedDay28). Measurements and Main Results: “M1-like” and pro-inflammatory gene sets such as IL-6-JAK-STAT5 signaling were significantly enriched in AMs isolated on Day 1 in Alive/ExtubatedDay28 versus Dead/IntubatedDay28 subjects. In contrast, by Day 8 many of these same pro-inflammatory gene sets were enriched in AMs collected from Dead/IntubatedDay28 compared with Alive/ExtubatedDay28 subjects. Serially-sampled Alive/ExtubatedDay28 patients were characterized by an AM temporal expression pattern of Day 1 enrichment of innate immune programs followed by prompt downregulation on Days 4 and 8. Dead/IntubatedDay28 subjects exhibited an opposite pattern, characterized by progressive upregulation of pro-inflammatory programs over the course of ARDS. The relationship between AM expression profiles and 28-day clinical status was distinct in subjects with Direct (pulmonary) versus Indirect (extrapulmonary) ARDS. Conclusion: Clinical outcomes in ARDS are associated with highly distinct AM transcriptional programs.