| Hyperoxia is routinely administered during mechanical ventilation for the management of severe respiratory distress. However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and compromises the ability of macrophages to migrate, phagocytose and kill bacteria. Previously, we showed that prolonged exposure to hyperoxia releases the nuclear protein high mobility group box-1 (HMGB1) into the airways. Extracellular HMGB1 mediates hyperoxia-induced pro-inflammatory lung injury and increases the mortality of mice infected with Pseudomonas aeruginosa (PA) via the impairment of macrophage phagocytosis. The aims of this study were to determine whether GTS-21 [3-(2,4 dimethoxybenzylidene)-anabaseine dihydrochloride], a partial alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonist, can significantly (1) inhibit HMGB1 accumulation in the airways to alleviate lung injury in a mouse model of ALI and, (2) attenuate hyperoxia-compromised macrophage phagocytosis to improve bacterial clearance in a mouse model of ventilator-associated pneumonia (VAP). GTS-21 (0.04, 0.4 and 4 mg/kg) or saline was administered via intraperitoneal injection to mice that were exposed to hyperoxia (≥99% 02). Administration of 4 mg/kg GTS-21 significantly decreased both the accumulation of airway HMGB1 and pro-inflammatory ALI, as indicated by a significant decrease in total protein content, neutrophil infiltration into the airways, and monocyte infiltration into the airways and lung interstitium. Furthermore, in a model of VAP, GTS-21 (4mg/kg) not only decreased ALI and accumulation of HMGB1 into the airways, but also significantly increased bacterial clearance. In order to determine the mechanism by which GTS-21 produces the aforementioned effects, RAW 264.7 cells, a macrophage like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% 02. Hyperoxiacompromised phagocytic activity of macrophages was significantly enhanced by GTS-21 via decreasing HMGB1 translocation into the cytoplasm and its subsequent release. Our results indicated that GTS-21 significantly attenuates ALI and increases bacterial clearance by enhancing macrophage functions via inhibiting the release of nuclear HMGB1. Therefore, the alpha7nAChR represents a possible therapeutic target for oxidative inflammatory lung injury in patients on ventilators by augmenting host defense against bacterial infections. |
