Acute respiratory distress syndrome (ARDS) in humans involves ≥ 200,000 individuals in the United States, and has a mortality rate (40%) for which no specific
drug has been approved for use in humans. We have studied experimental
acute lung injury (ALI) in mice following airway deposition of bacterial
lipopolysaccharide (LPS) or the recombinant mouse
complement anaphylatoxin, C5a. As ALI developed over 6 hr, extracellular
histones appeared in bronchoalveolar lavage fluids (BALF). Extracellular
histone appearance required both
C5a receptors (C5aR, C5L2) as well as neutrophils (PMNs) and lung macrophages, as genetic loss of either
C5a receptor or depletion of PMNs or macrophages reduced
histone levels found in BALF during ALI. It is possible that extracellular
histones were derived from formation of neutrophil extracellular traps (NETs) in lung after PMN contact with C5a. When purified
histones were delivered to lung via the airways, intense inflammatory injury ensued and type II cells developed large
blebs indicating cellular damage and apoptosis. Detailed physiological measurements revealed severe disruption of blood/alveolar gas exchange. These data suggest a key role for
histones in development of experimental ALI.