Genetic factors determine the contribution of leukotrienes to acute inflammatory responses

Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygen ase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence o f genetic factors on the contribution of LT to acute inflammation, we gener ated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA ) mouse lines. Topical application of AA evoked a vigorous inflammatory res ponse in 129 and DBA mice, whereas only a modest response was seen in B6 an imals. The response to AA in 129 and DBA strains is LT dependent. In contra st, LT make little contribution to this response in B6 mice. AA-induced inf lammation in B6 mice is prostanoid dependent, since this response was subst antially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous infla mmation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains, In contrast, the response to AA in the peritoneal cavi ty is robust in the 129 and B6 strains, but was significantly blunted in DB A mice, showing that strain differences in the response to AA are tissue sp ecific. Variations in these and other experimental models of inflammation a ppear to correlate directly with the ability of a particular mouse strain a nd a specific tissue to respond to LT, specifically LTC4. Taken together, t hese findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also be tween different tissues within these inbred mouse lines.