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

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.

Monocyte chemoattractant protein-1/CC chemokine ligand 2 enhances apoptotic cell removal by macrophages through Rac1 activation

“…anti-inflammatory mediators [1,2] and several key growth factors [2,3]. Efferocytosis of apoptotic polymorphonuclear neutrophils (PMNs) is crucial for resolution of acute inflammation in the lung [4,5].…”

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

“…Phagocytosis of apoptotic cells (efferocytosis) is integrally involved with the regulation of the inflammatory response and maintenance of lung homeostasis by 1) removing dead cells before the onset of necrosis (27), by 2) inducing release of anti-inflammatory mediators (27) and antiproteases (28), and by 3) increasing production of growth factors (29,30). Perhaps not surprisingly, impaired efferocytosis appears to be involved in the pathogenesis of a variety of chronic lung and systemic inflammatory diseases because it is defective in systemic lupus erythematosus, rheumatoid arthritis, cystic fibrosis, bronchiectasis, asthma, and chronic obstructive pulmonary disease (COPD) (31)(32)(33)(34)(35)(36)(37).…”

Inhibitory effects of persistent apoptotic cells on monoclonal antibody production in vitro

“…Although most studies to date have focused on the responses of macrophages that engulf apoptotic cells, evidence has been presented that exposure to apoptotic cells elicits repair responses, including growth factor and angiogenic factor production by neighbors. [14][15][16] Apoptotic cells directly produce factors such as IL-10, TGFβ-1 and lactoferrin 9,10,3 that can affect cell growth and differentiation. Furthermore, the presence of apoptotic cells has been found to initiate directional endothelial cell sprouting, an electrostatic mechanism resulting from the increased surface negative charge of apoptotic cells consequent to redistribution of phospholipids in their plasma membranes.…”