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

Rationale: Serial measurements of alveolar macrophage (AM) transcriptional changes in patients with acute respiratory distress syndrome (ARDS) could identify cell-specific biological programs that are associated with clinical outcomes. Objectives: To determine whether AM transcriptional programs are associated with prolonged mechanical ventilation and 28-day mortality in individuals with ARDS. Methods: We performed genome-wide transcriptional profiling of AMs purified from BAL fluid collected from 35 subjects with ARDS. Cells were obtained at baseline (Day 1), Day 4, and Day 8 after ARDS onset (N = 68 total samples). We identified biological pathways that were enriched at each time point in subjects alive and extubated within 28 days after ARDS onset (alive/extubated(Day28)) versus those dead or persistently supported on mechanical ventilation at Day 28 (dead/intubated(Day28)). Measurements and Main Results: M1-like (classically activated) and proinflammatory gene sets such as IL-6/JAK/STAT5 (Janus kinase/signal transducer and activator of transcription 5) signaling were significantly enriched in AMs isolated on Day 1 in alive/extubated(Day28) versus dead/intubated(Day28) subjects. In contrast, by Day 8, many of these same proinflammatory gene sets were enriched in AMs collected from dead/intubated(Day28) compared with alive/extubated(Day28) subjects. Serially sampled alive/extubated(Day28) subjects 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/intubated(Day28) subjects exhibited an opposite pattern, characterized by progressive upregulation of proinflammatory 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. Conclusions: Clinical outcomes in ARDS are associated with highly distinct AM transcriptional programs.