Alveolar Macrophages that Phagocytose Apoptotic Neutrophils Produce Hepatocyte Growth Factor during Bacterial Pneumonia in Mice

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Abstract
Hepatocyte growth factor (HGF) is postulated to play an important role in the repair of pulmonary epithelium in acute lung injury. To evaluate the role of HGF in bacterial pneumonia, the kinetics of HGF production and the cellular sources of HGF have been examined in the lungs of mice that had been intratracheally challenged with Pseudomonas aeruginosa. Neutrophil accumulation in the airway occurred immediately, reached a peak at 36 h, and then progressively declined by 14 d after infection. We found a biphasic pattern of HGF messenger RNA expression and protein synthesis in the lung after bacterial 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 epithelial cells. Interestingly, the second peak for HGF production, which was found around 48 to 72 h after infection, was closely associated with the increase in the percentage of alveolar macrophages (AMs) that became positive for myeloperoxidase, indicating phagocytosis of apoptotic neutrophils. The cellular source of the second peak was found to be AMs. Further, murine AMs which phagocytosed apoptotic neutrophils induced higher levels of HGF production in vitro. These results strongly indicate a novel mechanism of HGF production by AMs, which are phagocytosing apoptotic neutrophils, and the pivotal role of AMs in the healing and repair of damaged pulmonary epithelium through the production of HGF.