Effect of in vivo Coal Dust Exposure on Arachidonic Acid Metabolism in the Rat Alveolar Macrophage

"Oxygenated metabolites of arachidonic acid (MJ are produced by the alveolar macrophage (AM) and have been shown to mediate inflammatory reactions. We therefore assessed the production of eicosanoids by AM harvested from the lungs of rats ex· posed to a bituminous coal dust for 2 wk in an inhalation chamber in order to determine if AA metabolism was altered in a manner that may promote an inflammatory response in the lung. Exposure to coal dust resulted in a 66% increase in the number of AM harvested, an increase in thromboxane A2 (TxA;i) and leukotriene 84 (LTB,j) production to 222% and 181% of control values, respectively, and a decrease in prostaglandin E2 (PGE:i) production to '62% of control values. In AM harvested from rats allowed to breath clean air for 2 wk following coal dust exposure, PGE2 production returned to control levels but TxA2 and LTB4 production remained elevated. The TxA2 synthesis inhibitor UK 38,485 reduced TxA2 production in dust-exposed AM both immediately and 2 wk following exposure. Thus, exposure of rats to coal dust significantly alters the metabolism of AA in AM, with potentially important aspects of AA metabolism remaining altered even after a 2-wk recovery period. Based on the established role of eicosanoids in inflammatory and fibrotic processes, these results suggest that the alteration of AM eicosanoid production as a result of the inhalation of coal mine dust may be an important factor in the pathophysiology of coal workers' pneumoconiosis.The authors are grateful to Joan Greenwood and Barbara Scheetz for their excellent technical assistance and to Brenda Pavone for the preparation of the manuscript. This research was supported by the U.S. Department of The Interior's Mineral Institute Program administered through the Generic Mineral Technology Center for Respirable Dust under grant 1135142.Request for reprints should be sent to Douglas C. Kuhn, Ph.D., Department of Pathology, The M.S. Hershey Medical Center, Hershey, PA 17033.INTRODUCTIONPulmonary alveolar macrophages (AM) are activated by foreign particles and microorganisms that enter the small airways (Kass et al., 1966; Herscowitz, 1985). This defensive reaction involves phagocytosis, lysosomal enzyme release, and the generation of reactive oxygen species by the AM (Snella, 1986; Rich et al., 1987). A number of agents, including phorbol esters, zymosan, adenosine diphosphate, organic hydroperoxides, and calcium ionophore, have been shown to activate the AM in vitro (Badger, 1986; Marshall and Lands, 1986; Snella, 1986). The AM response to these activators appears to be mediated in part by the oxygenated metabolites of arachidonic acid (AA) (Bertram et al., 1988; Demers et al., 1987; Mcleish et al., 1987).The AM may metabolize AA through cyclooxygenase- and lipoxygenase- catalyzed pathways to produce a variety of eicosanoids including prostaglandin (PG) E2, thromboxane (Tx) A2, leukotriene (LT) B4, LTC4, LTD4, and several hydroxyeicosatetraenoic acid derivatives (HETEs) (Willis, 1970; Camp et al., 1983; Poubelle et al., 1986). The production of these eicosanoids may enhance the. defensive ability of the challenged lung since they stimulate chemotactic cell recruitment to the site of invasion, enhance extravasation of circulating immune cells, and promote local vasodilatation. However, continued stimulation of the AM population, with the consequent production of proinflammatory eicosanoids, may ultimately enhance the disease process by contributing to chronic bronchoconstriction, fibrosis, and the persistent release of toxic oxygen species."