Determination of the contribution of cysteinyl leukotrienes and leukotriene B-4 in acute inflammatory responses using 5-lipoxygenase- and leukotrieneA(4) hydrolase-deficient mice
Rs. Byrum et al., Determination of the contribution of cysteinyl leukotrienes and leukotriene B-4 in acute inflammatory responses using 5-lipoxygenase- and leukotrieneA(4) hydrolase-deficient mice, J IMMUNOL, 163(12), 1999, pp. 6810-6819
Arachidonic acid metabolism by 5-lipoxygenase leads to production of the po
tent inflammatory mediators, leukotriene (LT) B-4 and the cysteinyl LT, Rel
ative synthesis of these subclasses of LT, each with different proinflammat
ory properties, depends on the expression and subsequent activity of LTA(4)
hydrolase and LTC4 synthase, respectively. LTA(4) hydrolase differs from o
ther proteins required for LT synthesis because it is expressed ubiquitousl
y. Also, in vitro studies indicate that it possesses an aminopeptidase acti
vity. Introduction of cysteinyl LT and LTB4 into animals has shown LTB4 is
a potent chemoattractant, while the cysteinyl LT alter vascular permeabilit
y and smooth muscle tone. It has been impossible to determine the relative
contributions of these two classes of LT to inflammatory responses in vivo
or to define possible synergy resulting from the synthesis of both classes
of mediators. To address this question, we have generated LTA(4) hydrolase-
deficient mice, These mice develop normally and are healthy. Using these an
imals, we show that LTA(4) hydrolase is required for the production of LTB4
in an in vivo inflammatory response. We show that LTB4 is responsible for
the characteristic influx of neutrophils accompanying topical arachidonic a
cid and that it contributes to the vascular changes seen in this model. In
contrast, LTB4 influences only the cellular component of zymosan A-induced
peritonitis. Furthermore, LTA(4) hydrolase-deficient mice are resistant to
platelet-activating factor, identifying LTB4 as one mediator of the physiol
ogical changes seen in systemic shock. We do not identify an in vivo role f
or the aminopeptidase activity of LTA(4) hydrolase.