Characterization of Alveolar Macrophage Eicosanoid Production in a Non-Human Primate Model of Mineral Dust Exposure

"The relative activation of eicosanoid production which results from the exposure of the alveolar macrophage (AM) to mineral dusts is thought to be a key factor in the pathophysiology of occupational lung disease. We compared in vitro basal and silicastimulated production of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) by AM from normal humans and non-human primates (Macaca nemistrina). In addition, we instilled mineral dusts directly into one lung of the non-human primate and evaluated AM eicosanoid production at two week intervals following dust instillation. Unstimulated AM from humans produce more PGE2 and TXA2 than do AM from M. nemistrina. However, in vitro exposure of AM from both species to silica dust produced a qualitatively similar increase in TXA2 production accompanied by no change in PGE2 production. Sequential analysis of AM eicosanoid production following a single bolus exposure to bituminous or anthracite coal dusts, titanium dioxide (Ti()i) dust or crystalline silica showed marked variability among individual non-human primates in qualitative and quantitative aspects of dust-induced eicosanoid production. However, the rank order of potency of the different dusts (silica> anthracite> bituminous) correlated with epidemiological evidence relating the type of dust mined to the incidence of pneumoconiosis. These studies suggest that the non-human primate may serve as a model for the study of both the role of eicosanoids in the etiology of dust-induced occupational lung disease and the biochemical basis for individual variability in the response of lung cells to mineral dust exposure. IntroductionOccupational inhalation of mineral dust can lead to chronic debilitating lung disease ( 1,2). One of the key components of the disease process is thought to be the interaction of mineral dust with the alveolar macrophage (AM) and the subsequent release by the AM of inflammatory and fibrotic substances (3,4). Chronic inhalation of mineral dust, depending on the type and amount of dust, may then produce a situation in which ongoing inflammation, accompanied by the destruction of functional lung tissue by products of activated AM and polymorphonuclear neutrophils, stimulates the production of nonfunctional matrix by lung fibroblasts.The AM produces several oxygenated derivatives of arachidonic acid (AA) which may play important roles in dust-induced lung pathophysiology (5,6). In previous studies in the rat, we found that prostaglandin E2 (PGE2). thromboxane A2 (TXA2) and leukotriene 84 (L TB4) were the major AA metabolites produced by AM (7). PGE2 is associated with pro-inflammatory activity (8) as well as anti-fibrotic activity since it downregulates interleukin -1 (IL-1) and tumor necrosis factor (TNF) release by AM (9-11). TXA2 is known to stimulate platelet activity, cause bronchial and vascular smooth muscle contraction (12) and to possess chemotactic activity (13). LTB4 is chemotactic for neutrophils and monocytes (14) and has been suggested as an additional regulatory factor in the release of TNF by AM exposed to silica dust ( 15)."