Alveolar lining fluid regulates mononuclear phagocyte 5-lipoxygenase metabolism.

ABSTRACT

The enzyme 5-lipoxygenase (5-LO) catalyses the synthesis of leukotrienes (LT), which are important in phagocytosis and killing of microorganisms. The alveolar macrophage (AM), the primary resident defender of the alveolar space, has a greater capacity for LT synthesis than its precursor, the peripheral blood monocyte (PBM). This study investigated whether the alveolar lining fluid (ALF) upregulates LT synthetic capacity in mononuclear phagocytes. Rat AM, peritoneal macrophages (PM) and ALF were obtained by lavage from pathogen-free animals. Human PBM were isolated from normal subjects. 5-LO metabolism and expression were measured with and without ALF. Rat ALF increased 5-LO metabolism (136.4+/-15.1% of control) in cultured PBM. This was associated with increased 5-LO activating protein (FLAP) (357+/-29.5 %), and 5-LO expression (188+/-31.3%). Culture of AM for 3 days resulted in a greater decrement in LTB4 synthesis (LTB4 15.4+/-6.9% of day 1) than in PM (54.7+/-8.3% of day 1), suggesting a greater dependence of AM 5-LO metabolism on ALF. 5-LO and FLAP expression decreased to a greater degree in AM than PM in culture. Furthermore, AM cultured with ALF maintained their LT synthetic capacity, FLAP and 5-LO expression compared with control cells cultured in medium alone. In conclusion, alveolar lining fluid increased 5-lipoxygenase metabolism in peripheral blood monocytes and maintained it in cultured alveolar macrophages, by a mechanism of increased 5-lipoxygenase and 5-lipoxygenase activating protein expression. This may boost host defence capabilities.