BACKGROUND: Secretory immunoglobulin A (SIgA) is the specific immune antibacterial defense. Since pneumonia frequently complicates the course of trauma patients, we studied early airway immune responses after injury. METHODS: Twelve severely injured, intubated (expected for >/=5 d) patients had tracheal and bilateral lung lavage (BAL) within 30 hours of injury (n = 12). Epithelial lining fluid (ELF) volume and SIgA were measured by urea dilution and enzyme-linked immunosorbent assay (ELISA), respectively. Control BAL specimens were obtained from eight healthy elective surgical patients. Anatomically based comparisons were made between groups with Welch's unpaired t test. To verify human data, 30 male mice received no injury (time 0, n = 7) or injury with abdominal and neck incisions and were killed for airway IgA at 4 (n = 7), 8 (n = 8), and 24 (n = 8) hours. Analysis of variance (ANOVA) and Fisher's protected least significant difference testing was used to analyze animal data. RESULTS: Initial trauma patient SIgA concentration (SIgA/mL ELF) increased compared with control in the lungs bilaterally (p < 0.05 both right and left). ELF volume was significantly higher in the right lung (p = 0.02) and just missed statistical significance (p = 0.07) on the left. Mouse IgA increased 8 hours after stress (p < 0.05 versus 0, 4, and 24 hours) and returned to normal by 24 hours. CONCLUSION: A previously unrecognized innate human airway mucosal immune response with increased airway SIgA and ELF occurs after severe injury and is reproducible experimentally. This accessible, quantifiable human response allows study of clinical strategies to reduce infections via mucosal immune therapies.