leukotriene-e4 and Edema

The cysteinyl leukotrienes (cys-LTs) are a family of potent lipid mediators of inflammation derived from arachidonic acid. Activation of certain cell types results in the biosynthesis and export of leukotriene (LT) C(4), which then undergoes extracellular metabolism to LTD(4) and LTE(4). LTE(4), the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT(1)R and CysLT(2)R, respectively). We had recognized a greater potency for LTE(4) than LTC(4) or LTD(4) in constricting guinea pig trachea in vitro and comparable activity in eliciting a cutaneous wheal and flare response in humans. Thus, we hypothesized that a vascular permeability response to LTE(4) in mice lacking both the CysLT(1)R and CysLT(2)R could establish the existence of a separate LTE(4) receptor. We now report that the intradermal injection of LTE(4) into the ear of mice deficient in both CysLT(1)R and CysLT(2)R elicits a vascular leak that exceeds the response to intradermal injection of LTC(4) or LTD(4), and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE(4) is approximately 64-fold more potent in the CysLT(1)R/CysLT(2)R double-deficient mice than in sufficient mice. The administration of a CysLT(1)R antagonist augmented the permeability response of the CysLT(1)R/CysLT(2)R double-deficient mice to LTC(4), LTD(4), and LTE(4). Our findings establish the existence of a third receptor, CysLT(E)R, that responds preferentially to LTE(4), the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.

Topics: Animals; Capillary Permeability; Edema; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Mice; Mice, Knockout; Receptors, Leukotriene

The actions of cysteinyl leukotrienes include production of oedema. We investigated whether these mediators might be involved in the oedematous malnutrition syndrome kwashiorkor. The capacity of leukotriene (LT) synthesis by stimulated whole blood and urinary LTE4 excretion was measured in 12 children with kwashiorkor, and compared with that in 24 marasmic and 12 control children. Urinary LTE4 excretion was significantly higher in patients with kwashiorkor than in controls (118.8 [SD 28.5] vs 31.1 [19.3] nmol/mol creatinine; p < 0.01). Whole blood LTE4 synthesis was increased in kwashiorkor patients by a factor of 3.5 (p < 0.01). In marasmic children, LTE4 excretion and synthesis did not differ from those in controls. Although glutathione, known to participate in LTC4 synthesis, was subnormal in erythrocytes of all malnourished patients, whole-blood LTC4 synthesis was higher in kwashiorkor patients than in controls (28.1 [5.0] ng/mL; p < 0.05), and close to control values (9.8 [1.5] ng/mL) in marasmic children. LTB4 synthesis, however, was greatly reduced in kwashiorkor patients (11.5 [2.4] vs 46.5 [6.4] ng/mL; p < 0.01). Inability to synthesise the immunoregulator LTB4 may lead to inefficient chemoattraction of phagocytes and an inadequate inflammatory response in kwashiorkor. The increased endogenous cysteinyl LT generation in kwashiorkor suggests that these lipid mediators are involved in the pathophysiology of the syndrome, particularly in oedema formation.

Topics: Child, Preschool; Edema; Glutathione; Health Status; Humans; Infant; Kwashiorkor; Leukotriene E4