Determination of the contribution of cysteinyl leukotrienes and leukotriene B-4 in acute inflammatory responses using 5-lipoxygenase- and leukotrieneA(4) hydrolase-deficient mice

Citation
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
Citations number
51
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
163
Issue
12
Year of publication
1999
Pages
6810 - 6819
Database
ISI
SICI code
0022-1767(199912)163:12<6810:DOTCOC>2.0.ZU;2-K
Abstract
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.