Cytokines in Metal Fume Fever

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Abstract
Metal fume fever is a flulike illness caused by zinc oxide inhalation and accompanied by an impressive pulmonary cellular response. We hypothesized that the syndrome is mediated by cytokines released in the lung after exposure to zinc oxide fume. We carried out 26 experimental welding exposures in 23 volunteer subjects, performing postexposure bronchoalveolar lavage (BAL) 3 h (n = 6), 8 h (n = 11), or 22 h (n = 9) after exposure. We detected tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) varying in a time- and exposure-related manner. The concentration of TNF in the BAL fluid supernatant was significantly greater at 3 h than at 8 h or 22 h after exposure (p < 0.05), exhibiting a statistically significant exposure-response relationship to airborne zinc at each follow-up time period (p < 0.05). TNF concentrations were statistically correlated with those of IL-6 in BAL supernatant obtained at 22 h (r = 0.78, p = 0.01) and with concentrations of IL-8 in BAL 8 h after exposure (r = 0.85, p = 0.001). IL-6 displayed a significant exposure-response relationship to zinc (p < 0.05) at 22 h. IL-8 exhibited a significant exposure-response relationship to zinc (p < 0.05) at 8 h after exposure, a time at which IL-8 correlated with marked increases in BAL fluid polymorphonuclear leukocytes (PMN) (r = 0.7, p = 0.01). Although we also detected interleukin-1 (IL-1) in BAL samples, this cytokine did not demonstrate a statistically significant exposure response. TNF, IL-6, and IL-8 in BAL fluid supernatant concentrations increased in a time and exposure-dependent fashion after zinc oxide welding fume exposure. The time course of increased cytokines, their correlations with one another and with PMN in the BAL fluid, and the consistency of our findings with the known kinetics and actions of these cytokines support the hypothesis that a network of cytokines is involved in the pathogenesis of metal fume fever.