Cell-free hemoglobin triggers macrophage cytokine production via TLR4 and MyD88.

Cell-free hemoglobin (CFH) is elevated in the airspace of patients with acute respiratory distress syndrome (ARDS) and is sufficient to cause acute lung injury in a murine model. However, the pathways through which CFH causes lung injury are not well understood. Toll-like receptor 4 (TLR4) is a mediator of inflammation after detection of damage- and pathogen-associated molecular patterns. We hypothesized that TLR4 signaling mediates the pro-inflammatory effects of CFH in the airspace. After intra-tracheal CFH, BALBc mice deficient in TLR4 had reduced inflammatory cell influx into the airspace (bronchoalveolar lavage [BAL] cell counts, median TLR4KO:0.8x10