Reviews and feature article
The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications

https://doi.org/10.1016/j.jaci.2009.05.046Get rights and content

The intracellular parent of the cysteinyl leukotrienes (cysLTs), leukotriene (LT) C4, is formed by conjugation of LTA4 and reduced glutathione by LTC4 synthase in mast cells, eosinophils, basophils, and macrophages. After extracellular export, LTC4 is converted to LTD4 and LTE4 through sequential enzymatic removal of glutamic acid and then glycine. Only LTE4 is sufficiently stable to be prominent in biologic fluids, such as urine or bronchoalveolar lavage fluid, of asthmatic individuals and at sites of inflammation in animal models. LTE4 has received little attention because it binds poorly to the classical type 1 and 2 cysLT receptors and is much less active on normal airways than LTC4 or LTD4. However, early studies indicated that LTE4 caused skin swelling in human subjects as potently as LTC4 and LTD4, that airways of asthmatic subjects (particularly those that were aspirin sensitive) were selectively hyperresponsive to LTE4, and that a potential distinct LTE4 receptor was present in guinea pig trachea. Recent studies have begun to uncover receptors selective for LTE4: P2Y12, an adenosine diphosphate receptor, and CysLTER, which was observed functionally in the skin of mice lacking the type 1 and 2 cysLT receptors. These findings prompt a renewed focus on LTE4 receptors as therapeutic targets that are not currently addressed by available receptor antagonists.

Section snippets

Discovery of LTE4

The slow-reacting substance of anaphylaxis (SRS-A), so named by Brocklehurst,1 was identified as a substance generated by in vitro antigen/allergen challenge of perfused lungs of actively sensitized guinea pigs or human lung fragments of allergic patients requiring resection. Its potent constrictor activity on guinea pig or human bronchioles in the presence of an antihistamine provided compelling evidence for its potential role in asthma. The initial analyses into the physical characteristics

Early pharmacology of LTE4 in animals

The potency of LTE4 for contraction of guinea pig tracheal spirals in vitro was 10-fold greater than that of either LTC4 or LTD4, whereas for guinea pig parenchymal strips, the potency of LTD4 was 6-fold that of LTE4 and 20-fold that of LTC4. Furthermore, the concentration effect for LTD4 and LTE4 on parenchymal strips observed by Drazen et al12 was biphasic, with the initial low concentration effect (studied only for LTD4) being competitively antagonized by FPL55712. In contrast, LTC4 was the

Early studies of LTE4 metabolism

The products of the granulocyte respiratory burst, which are abundant with inflammation, can alter the stability of each cysLT in vitro and in vivo. Phorbol 12-myristate 13-acetate–activated human neutrophils converted each cysLT to their subclass-specific S-diastereoisomeric sulfoxides, which retained their ability to be detected by cysLT–specific antibodies but lost greater than 95% of function. Each sulfoxide was further processed to identical diastereoisomers of 6-trans LTB4, which were

Early pharmacology of LTE4 in human subjects

Although the early pharmacology of the 3 sequentially generated cysLTs identified LTE4 as the most stable in physiologic and pathobiologic models, clinical attention shifted to LTD4 and LTC4, which on inhalation were up to 1000 times as potent as histamine.21, 22 LTE4 was only 39 times as potent as histamine in reducing maximum expiratory flow at 30% of vital capacity in healthy human subjects.21, 22, 23 Although each cysLT was a potent bronchoconstrictor in patients with bronchial asthma,

Functional and pharmacologic characterization of CysLTER, a cutaneous receptor preferential for LTE4

In addition to addressing the pharmacology of the cysLTs during the 1980s, we began to characterize LTC4S, the integral protein of the outer nuclear membrane responsible for biosynthesis of LTC4, by means of conjugation of glutathione to LTA4.7 After expression cloning of human LTC4S and then homology cloning of murine LTC4S,27, 28 we turned to targeted disruption of murine LTC4S to explore for phenotypic characteristics that might depend on the functions of the cysLTs.29 In a model of passive

Discovery that the P2Y12 receptor mediates mast cell activation and pulmonary inflammation by LTE4

As is the case for many effector cells of bone marrow origin, mast cells express both CysLT1R and CysLT2R.35, 36 LTC4 and LTD4 both induce calcium flux, cytokine and chemokine generation, phosphorylation of extracellular signal-regulated kinase (ERK), and proliferation of human mast cells in vitro.35, 36, 37 These responses, like those of the cutaneous microvasculature, are regulated positively by CysLT1R but negatively regulated by CysLT2R based on experiments in which each receptor is

Epilogue

At this early stage, clinical considerations must be circumspect and limited based on these findings for receptors in naive mice in model systems or with targeted disruption of classical receptors. Nonetheless, the history of cysLT-mediated permeability effects in guinea pigs and human subjects suggests that this important aspect of the inflammatory process is as responsive to LTE4 as to its precursors, LTC4 and LTD4, which are only transiently present during an inflammatory process. The

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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Terms in boldface and italics are defined in the glossary on page 407.

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