Alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice

Hepatocyte growth factor (HGF) is postulated to play an important role in t he repair of pulmonary epithelium in acute lung injury. To evaluate the rol e of HGF in bacterial pneumonia, the kinetics of HGF production and the cel lular sources of HGF have been examined in the lungs of mice that had been intratracheally challenged with Pseudomonas aeruginosa. Neutrophil accumula tion in the airway occurred immediately, reached a peak at 36 h, and then p rogressively declined by 14 d after infection. We found a biphasic pattern of HGF messenger RNA expression and protein synthesis in the lung after bac terial infection. The first peak for HGF production was found at 6 h after infection, and the primary source of HGF was shown to be bronchial epitheli al cells. Interestingly, the second peak;for HGF production, which was foun d around 48 to 72 h after infection, was closely associated with the increa se in the percentage of alveolar macrophages (AMs) that became positive for myeloperoxidase, indicating phagocytosis of apoptotic neutrophils. The cel lular source of the second peak was found to be AMs. Further, murine AMs wh ich phagocytosed apoptotic neutrophils induced higher levels of HGF product ion in vitro. These results strongly indicate a novel mechanism of HGF prod uction by AMs, which are phagocytosing apoptotic neutrophils, and the pivot al role of AMs in the healing and repair of damaged pulmonary epithelium th rough the production of HGF.