Basic Science for the Practicing ClinicianLipid mediators and allergic diseases
Introduction
Lipids are a primary nutrient energy source and the major components of the cell membranes of all organisms. Lipid molecules also can function in intercellular signaling and have important roles in inflammatory and immune responses and in the regulation of many normal cellular functions and homeostasis. Prostaglandins (PGs), leukotrienes (LTs), and a variety of other lipid molecules with such signaling roles are known as lipid mediators or bioactive lipids. These molecules are synthesized on demand from precursor membrane lipids and act primarily by binding to G protein-coupled receptors (GPCRs).1
The importance of lipid mediators as diagnostic markers and therapeutic targets in allergic diseases has been long recognized and continues to evolve. This is particularly true of asthma, for which there is the largest and broadest body of published literature among the allergic diseases. This review provides an overview of the pathways of lipid mediator generation and examines the relevance of specific lipid mediators to the pathobiology of allergic inflammation and implications for current and future clinical management of allergic diseases. Although lysophospholipids, lipoxins, and other lipids are relevant to the mechanisms of allergic inflammation, this review focuses on PGs and LTs because of the abundance of existing literature, including clinical data, regarding these mediators. A summary of the mediators discussed in this review is presented in Table 1.
Section snippets
Generation of Lipid Mediator Precursors
Enzymes known as phospholipases A2 release arachidonic acid from the sn-2 position (ie, the second carbon of the glycerol molecule) of membrane phospholipids, also resulting in the formation of lysoglycero-phospholipids.2 Arachidonic acid is oxidatively metabolized by the cyclooxygenase and lipoxygenase pathways and is thereby the precursor for all PGs and LTs.3 These mediators are known as eicosanoids and are named for eikosi, the Greek word for 20, because arachidonic acid has 20 carbon atoms.
Overview of the Cyclooxygenase Pathway
There are 2 cyclooxygenase (COX) enzyme isoforms: COX-1 and COX-2. These enzymes originate from different genes and have distinct tissue-specific expressions and biologic functions. Expression of COX-1 is constitutive in most tissues and believed to have a role in homeostasis. COX-2 expression is inducibly expressed by hematopoietic and nonhematopoietic cells in response to a variety of stimuli and is associated with inflammation and disease states.[3], [5], [6]
COX-1 and COX-2 catalyze 2
PGD2 and Its Receptors, DP1 and DP2/Chemoattractant Homologous Molecule Expressed on TH2 Cells
Prostaglandin D2 is released in large quantities by mast cells in response to IgE-mediated activation.19 Other leukocytes, including TH2 cells20 and dendritic cells (DCs),21 produce PGD2 at lower levels. PGD2 signals through receptors DP1 and DP2 (also known as chemoattractant homologous molecule expressed on TH2 cells [CRTH2]).22 Aerosolized PGD2 administered to sensitized mice before antigen challenge increased the numbers of eosinophils and the levels of TH2 cytokines found in BAL fluid.23
Overview of the 5-LO Pathway
As for the COX pathway, arachidonic acid is the precursor for the 5-LO pathway. Arachidonic acid is first oxidized to 5-hydroxyperoxyeicosatetraenoic acid and then dehydrated to leukotriene A4 (LTA4), an unstable precursor, by 5-LO.[48], [72] The generation of LTA4 by 5-LO also depends on the function of 5-LO activating protein, a perinuclear membrane protein that transfers free arachidonic acid to 5-LO.48 Two different classes of LTs can be produced from LTA4. LTB4 is formed by LTA4 hydrolase,
Cys-LTs and Their Receptors
The Cys-LTs function by signaling through at least 3 GPCRs: CysLT1R, CysLT2R,72 and the recently reported CysLT3R.88 CysLT1R binds LTD4 with highest affinity and LTC4 and LTE4 with lower affinity. CysLT2R has equal affinity for LTC4 and LTD4 and lower affinity for LTE4.89 CysLT3R exhibits a strong binding preference for LTE4, the most stable and abundant cys-LT.88 CysLT1R and CysLT2R are each expressed by bronchial smooth muscle and various cells of the immune system.89 Patients with AERD had
Discussion
Lipid mediators have important roles in the pathophysiology of disease and the maintenance of homeostasis. In addition to their role in the development of acute inflammation, lipid mediators influence innate and adaptive immunities through complex signaling networks. The effectiveness of existing therapies, such as CysLT1R antagonists and 5-LO inhibitors for asthma, demonstrates the importance of lipid mediators in human allergic disease. The identification of novel receptors not only helps to
Conclusions
Lipid mediators can have pro- and anti-inflammatory effects in allergic disease and asthma. These molecules, including PGs and LTs, are important as diagnostic markers and therapeutic targets. The development of new therapeutic agents for allergic disease will evolve from a rapidly expanding understanding of these mediators, their receptors, and the context within which they function.
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Disclaimers: Dr Boyce has received honoraria from Merck.