The Inflammatory Response and Resistance to Endotoxin in Mice

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Abstract
Endotoxin lipopolysaccharide is a potent inflammatory agent which produces many pathophysiologic effects in mice. One strain of mice, C3H/Hej, is unique in its responses to endotoxin in that, in contrast to other mice, it possesses a high degree of resistance to endotoxin lethality, does not support an in vitro mitogenic response to endotoxin, and produces a small immune response to endotoxin in vivo. To see if the in vivo inflammatory responses produced by endotoxin in the resistant and normally susceptible mice were consistent with the above dichotomies, we investigated the kinetics of the i.p. inflammatory response to endotoxin in C3H/Hej mice vs normally susceptible strains. Paradoxically, the C3H/Hej mice responded with a rapid i.p. influx of PMN which peaked at 12 hr. This was followed by an influx of macrophages which peaked at 48 hr. In susceptible strains, the maximum PMN and macrophage responses were at 96 hr and were at least 80% less in response to the four types of LPS tested at wide dose ranges. Other inflammatory agents, such as proteose peptone, PHA, zymosan, or inulin failed to demonstrate differences between susceptible and resistant mice. In attempting to delineate the mechanism(s) responsible for the widely different responses to LPS, we found that in all strains the serum C titers were equal; the levels of chemotactic activity produced by LPS in sera in vitro were equal; and the chemotactic capabilities in vitro of the PMN were equal. In comparing the inflammatory responses generated in the resistant and susceptible mice to native endotoxin, lipid A-KDO glycolipid, and lipid A, it was determined that the carbohydrate moieties of the native endotoxin molecule were necessary for the preservation of the large differential inflammatory responses seen in the C3H/Hej and normal mice. Finally, we demonstrated that the survival of susceptible mice challenged with endotoxin i.p. could be enhanced by augmenting the magnitude of the i.p. inflammatory response via simultaneous injection of a second inflammatory agent. Thus, the rapid influx of inflammatory cells in the C3H/Hej mouse may be integrally related to its endotoxin resistance.

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