Eicosanoid and Cytokine Production by the Pulmonary Alveolar Macrophage

"Eicosanoids and cylokines produced by the pulmonary alveolar macrophage (PAM) are key mediators for the defensive role this cell plays in neutralizing the inhalation of particulate dusts and foreign microbes. However, these factors are also mediators of inflammation and their uncontrolled release may cause the lung injury and liorotic changes observed in individuals exposed occupationally to mineral dust. In vitro studies have suggested a link between the production of certain eicosanoids and cylokines released from the activated PAM. To this end, we have studied the release of eicosanoids (PGE2, TXB2 and LTB4) and cylokines (IL-1 and TNF) by cultured PAM, obtained from healthy human volunteers by bronchoalveolar lavage under basal culture conditions and following acute exposure to provocative agents such as the endotoxin lipopolysaccharide (LPS) and mineral dusts including silica. Studies were also carried out in the presence of specific cyclooxygenase inhibitors. The addition of LPS (10 µg/ml) to the culture medium produced a significant increase in PAM release of the eicosanoids: PGE2 (3.5 fold over baseline), TXB2 (2.8 fold over baseline) and LTB4 (4 fold over baseline). LPS also elicited a 2.5 fold elevation in IL-1 from these cells and a 9 fold increase in TNF release. The cyclooxygenase inhibitor, ibuprofen, significantly inhibited the LPS-induced rise in PGE2, TXB2 and TNF but had only a modest suppressive effect on IL-1 release. Exposure of these cells to silica dust elicited a similar augmentation in eicosanoid and cylokine release which was neutralized by prior exposure of the cells to ibuprofen. These results suggest that the enhanced production of eicosanoids and cytokines by PAM exposed to endotoxins and/or mineral dusts may be linked and that inhibition of eicosanoid release is linked to the production of TNF. IL-1 release however is not effectively neutralized by cyclooxygenase inhibition.INTRODUCTIONThe initial pulmonary cellular response to inhaled mineral dust involves the elaboration of potent inflammatory mediators from the pulmonary alveolar macrophage (1). These mediators include the eicosanoids (oxygenated metabolites of arachidonic acid) and cytokines (intercellular peptides) which are released into the alveolar space by the interaction of mineral dust with the PAM surface membrane. The eicosanoids and cytokines promote local nonvascular and vascular smooth muscle contractility changes, elicit the recruitment of additional mononuclear cells into the alveolar space, and enhance the activation, growth and differentiation of lung fibroblasts (2). In this study we sought to examine whether eicosanoid release and metabolism are linked to cytokine release when PAM are activated upon exposure to endotoxin or mineral dusts. Modulation of these pathways through inhibitory pharmaceutical agents may help attenuate the Injurious effects caused by a sustained release of these proinftammatory intercellular factors (3). To that end, we have studied the in vitro effects of endotoxin and silica on eicosanoid and cytokine release from cultured PAM obtained from healthy human volunteers."