NEWBORN MICE DIFFER FROM ADULT MICE IN CHEMOKINE AND CYTOKINE EXPRESSION TO OZONE, BUT NOT TO ENDOTOXIN

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Abstract
Neonatal animals of some mammalian species are more tolerant to several pulmonary oxidative stress-inducing toxicants than adults. Our initial studies during hyperoxic injury demonstrated a rapid chemokine and cytokine response early in the development of injury in newborn mice, whereas adult mice demonstrated little alteration in cytokine abundance until lethality was imminent. Our hypothesis is that altered response between newborn and adult mice is associated with differential cell injury, rather than alterations in the regulation of the inflammatory response. To test this hypothesis we utilized two distinct models of inducing pulmonary toxicity: ozone (O3), which causes epithelial cell injury, and endotoxin, which causes pulmonary inflammation independent of direct epithelial cell injury. C57Bl/6J mice (36 h or 8 wk old) were exposed to O3 at 1 or 2.5 ppm for 4, 20, or 24 h or to a 10-min inhalation of 10 ng endotoxin per mouse (estimated deposited dose) and were examined 2, 6, or 24 h postexposure. Adult mice displayed increased sensitivity to O3, as demonstrated by increased abundance of mRNAs encoding eotaxin, macrophage inflammatory protein (MIP)-1a, MIP-2, interleukin (IL)-6, and metallothionein (Mt). In newborn mice, only Mt was increased after 4 h of exposure. In contrast, newborn and adult mice responded similarly at 2 h post endotoxin exposure, inducing messages encoding tumor necrosis factor (TNF)- a, eotaxin, MIP-1a, MIP-1b, MIP-2, interferon inducible protein (IP)-10, and monocyte chemoattractant protein (MCP)-1. Furthermore, interleukin-6 (IL-6) was increased in adults but not newborns. Similar chemokine and cytokine responses of newborn and adult mice in response to an agent not causing epithelial injury (endotoxin) suggest that altered inflammatory control observed between newborn and adult mice following O3 exposure is secondary to epithelial cell injury.