SEQUENTIAL EXPOSURES TO OZONE AND LIPOPOLYSACCHARIDE IN POSTNATAL LUNG ENHANCE OR INHIBIT CYTOKINE RESPONSES

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Abstract
Sequential exposures to inhaled environmental pollutants may result in injuries/responses not predicted by evaluating exposures to an individual toxicant. This may indicate that the lung is damaged or primed by earlier events, so exposure to a nontoxic dose of an environmental pollutant may be sufficient to trigger adverse responses. The present study was designed to test the hypothesis that stimulating lung epithelial damage or inflammatory cell activation followed by a second stimulus leads to responses not seen after individual exposures in the postnatal lung. C57Bl/6 mice ages 4, 10, and 56 days were exposed to either a 10-minute inhalation of lipopolysaccharide (LPS), with an estimated deposited dose of 26 EU, followed immediately by 2.5 PPM ozone for 4 hours, or to 2.5 PPM ozone for 4 hours followed immediately by a 10-minute inhalation of LPS and examined 2 hours post exposure. Abundance of proinflammatory cytokine messages was measured by RNase protection assay. Exposure to LPS followed by ozone induced an inflammatory response in 4-day-old mice, which was not detected after LPS or ozone exposure alone. This exposure sequence also generated a synergistic increase in interleukin (IL)-6 mRNA abundance in 10- and 56-day-old mice but not in 4-day-old mice. Exposure to ozone followed by LPS inhibited IL-1α and IL-1β responses in 4-, 10-, and 56-day-old mice; furthermore, this inhibitory effect was observed after 1.0 and 0.5 PPM ozone exposures. These results demonstrate that preexposure to LPS, which primarily activates inflammatory cell recruitment, can cause sensitization to a secondary stimulus. However, preexposure to ozone, which primarily damages the epithelium, inhibited proinflammatory responses. Thus it was concluded that sequential exposures to ozone and LPS resulted in responses not predicted by evaluating individual exposures during postnatal lung development.