Critical time points in the response of postnatal lung to inhaled pollutants
Johnston, Carl James
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Age appears to be a critical variable in the ability of the lung to cope with external stress. Alterations in cellular responses associated with environmental toxicants are likely to modify the developmental processes, suggesting that the timing and interaction between exposure and developmental events play an important role as susceptible targets for environmental perturbation. Combined exposures to multiple environmental pollutants may result in injuries/responses not predicted by evaluating exposures to individual pollutants. This may indicate that the lung is damaged or primed by earlier events so exposure to a non-toxic dose of an environmental pollutant may be sufficient to trigger adverse responses including increased inflammatory cell recruitment, epithelial cell damage and toxicity. The following objectives tested the hypothesis in newborn, juvenile and adult mice during exposure to low levels of inhaled LPS and ozone: (1) Compare newborn vs. adult responses to environmental agents to determine critical periods of development, (2) Examine how induction of lung epithelial damage or inflammatory cell activation followed by a second stimulus compares to responses after individual exposures in the postnatal lung, (3) Evaluate the role of early signaling cascades induced during acute injury. We exposed C57B1/6 mice varying in age from 2 thru 56 days. Mice were exposed to 0.5, 1 or 2.5 ppm ozone for 4 hours or LPS via inhalation and examined 0.5, 1, 2 or 4 hours post exposure. Tissue injury was determined by histological examination and analysis of epithelial and inflammatory markers. Proinflammatory, chemokine, antioxidant and early response genes were analyzed for changes in message abundance by RNase Protection Assay and immunohistochemical analysis. These results demonstrated that critical time points exist during lung development to inhaled environmental pollutants and that differences exist in the maturation of inflammatory and epithelial defense mechanisms. Furthermore, sequential exposures to ozone and LPS resulted in responses not predicted by evaluating individual exposures during postnatal lung development. Finally, sequential exposures induced multiple signaling pathways which were age dependent, leading to responses not predicted by individual exposures during postnatal lung development.