Inflammatory and Fibrotic Mediator Release by Alveolar Macrophages from Coal Miners

"Eicosanoids and cytokines produced by alveolar macrophages (AM) are key mediators of pulmonary inflammation and fibrosis. In order to determine if eicosanoid production and cytokine production are altered in AM obtained from coal miners, we compared production of prostaglandin E2 (PCE2), thromboxane A2 (TXA2), leukotriene B4 (LTB4), interleukin-1 beta (IL-1B ), and tumor necrosis factor alpha (TNfa.) by cultured AM from normal human subjects and coal miners. The recovery of AM from miners' lungs by bronchoalveolar lavage was significantly greater than that from control subjects. Mean eicosanoid and cytokine production by AM from active miners was also increased compared to AM from control subjects, but this increase was not statistically significant. AM from control subjects produced significantly more TXA2 and TNFa. when exposed to lipopolysaccharide than did AM from miners. The cyclooxygenase inhibitor suprofen reduced PGE1 and TXA1 production and TNF0t. release but had no effect on LTB4 production or IL-1B release by miners' AM. The lipoxygenase inhibitor nordihydroguaiaretic acid attenuated TNFa release, as well as that of LTB4, but had no effect on IL-1B release. Inhibition of thromboxane synthase by UK 38,485 also reduced TNFa release by active miners ' AM but had no effect on PGE1, LTB, production, or IL-1 f3 release. The results of these studies suggest that occupational inhalation of coal dust may increase total lung eicosanoid and cytokine levels and reduce the reactivity of AM to bacterial endotoxin. Furthermore, coal dust-induced changes in both eicosanoid and cytokine release may be subject to pharmacological modulation.The alveolar macrophage (AM) is a primary defensive cell in the lung and is one of the first cell types to encounter inhaled mineral dust. The response of the AM to invading foreign material is designed to enhance the defensive capacity of the lung. However, in the case of occupational inhalation of mineral dust particles, this response may be inappropriate, resulting not in the defense of the lung but in chronic inflammation and fibrosis (Rom et al., 1987; Takemura et al., 1989). The reaction of the AM to chronic mineral dust exposure may involve the exaggerated release of paracrine mediators of lung function, including eicosanoids (oxygenated derivatives of arachidonic acid) and peptides, including cytokines and growth factors (Sibille & Reynolds, 1990). Eicosanoids are involved in bronchial and vascular smooth muscle reactivity, vascular permeability, fibroblast growth, and the recruitment of additional immune cells to the alveolar space (Barnard et al., 1992; Elias et al., 1985; Scott et al., 1982). AM-derived cytokines such as interleukin-1 beta (IL-1 B) and tumor necrosis factor alpha (TN Fa) have a variety of biological activities including the regulation of fibroblast growth and proliferation (Becker et al., 1989; Libby et al., 1989; Schmidt et al., 1984). Interestingly, in vitro studies with macrophages suggest that the production of cytokines may be linked to eicosanoid production, in particular that prostaglandin E2 (PGE2) may down-regulate IL-1 f3 and TN Foe production by the AM (Bonta et al., 1989; Kunkel et al., 1986; Monick et al., 1987)."