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

<b>Rationale:</b> 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.<b>Objectives:</b> To determine whether AM transcriptional programs are associated with prolonged mechanical ventilation and 28-day mortality in individuals with ARDS.<b>Methods:</b> 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 (<i>N</i> = 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).<b>Measurements and Main Results:</b> "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.<b>Conclusions:</b> Clinical outcomes in ARDS are associated with highly distinct AM transcriptional programs.