Lipid mediators and allergic diseases

doi:10.1016/j.anai.2013.06.031

Annals of Allergy, Asthma & Immunology

Volume 111, Issue 3, September 2013, Pages 155-162

https://doi.org/10.1016/j.anai.2013.06.031 Get rights and content

Abstract

Objective

To review the basic science and translational relevance of lipid mediators in the pathobiology of allergic diseases.

Data Sources

PubMed was searched for articles using the key terms lipid mediator, prostaglandin, prostanoid, leukotriene, thromboxane, asthma, and allergic inflammation.

Study Selections

Articles were selected based on their relevance to the goals of this review. Articles with a particular focus on clinical and translational aspects of basic science discoveries were emphasized.

Results

Lipid mediators are bioactive molecules generated from cell membrane phospholipids. They play important roles in many disease states, particularly in inflammatory and immune responses. Lipid mediators and their receptors are potentially useful as diagnostic markers of disease and therapeutic targets.

Conclusions

Several useful therapeutic agents have been developed based on a growing understanding of the lipid mediator pathways in allergic disease, notably the cysteinyl leukotriene receptor type 1 antagonists and the 5-lipoxygenase inhibitor, zileuton. Additional receptor agonists and antagonists relevant to these pathways are in development, and it is likely that future pharmacologic treatments for allergic disease will become available as our understanding of these molecules continues to evolve.

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 T_H2 Cells

Prostaglandin D₂ is released in large quantities by mast cells in response to IgE-mediated activation.¹⁹ Other leukocytes, including T_H2 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 T_H2 cells [CRT_H2]).²² Aerosolized PGD₂ administered to sensitized mice before antigen challenge increased the numbers of eosinophils and the levels of T_H2 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.

References (108)

R.H. Schaloske et al.
The phospholipase A2 superfamily and its group numbering system
Biochim Biophys Acta
(2006)
Y.J. Kang et al.
Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation
Prog Lipid Res
(2007)
B.L. Diaz et al.
Phospholipase A(2)
Prostaglandins Leukot Essent Fatty Acids
(2003)
T. Hirata et al.
Prostanoids as regulators of innate and adaptive immunity
Adv Immunol
(2012)
M.C. Liu et al.
Effects of prednisone on the cellular responses and release of cytokines and mediators after segmental allergen challenge of asthmatic subjects
J Allergy Clin Immunol
(2001)
R.G. Townley et al.
CRTH2 antagonists in the treatment of allergic responses involving TH2 cells, basophils, and eosinophils
Ann Allergy Asthma Immunol
(2012)
D. Proud et al.
Inflammatory mediator release on conjunctival provocation of allergic subjects with allergen
J Allergy Clin Immunol
(1990)
W.W. Busse et al.
Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients
J Allergy Clin Immunol
(2013)
C. Benyahia et al.
PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy?
Pulm Pharmacol Ther
(2012)
H. Aizawa et al.
Effects of thromboxane A2 antagonist on airway hyperresponsiveness, exhaled nitric oxide, and induced sputum eosinophils in asthmatics
Prostaglandins Leukot Essent Fatty Acids
(1998)

M. Hoshino et al.

Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma

J Allergy Clin Immunol

(1999)

T.M. Laidlaw et al.

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Blood

(2012)

C. Mondino et al.

Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children

J Allergy Clin Immunol

(2004)

M.C. Liu et al.

Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group

J Allergy Clin Immunol

(1996)

A. Di Gennaro et al.

The leukotrienes: immune-modulating lipid mediators of disease

Adv Immunol

(2012)

Y. Kanaoka et al.

Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand

J Biol Chem

(2013)

Y. Jiang et al.

CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells

Blood

(2007)

T. Shimizu

Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation

Annu Rev Pharmacol Toxicol

(2009)

W.L. Smith et al.

Why there are two cyclooxygenase isozymes

J Clin Invest

(2001)

T.D. Warner et al.

Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic

FASEB J

(2004)

D.C. Zeldin et al.

Airway inflammation and responsiveness in prostaglandin H synthase–deficient mice exposed to bacterial lipopolysaccharide

Am J Respir Cell Mol Biol

(2001)

M.A. Carey et al.

Accentuated T helper type 2 airway response after allergen challenge in cyclooxygenase-1−/− but not cyclooxygenase-2−/− mice

Am J Respir Crit Care Med

(2003)

J. Nakata et al.

Augmentation of allergic inflammation in the airways of cyclooxygenase-2–deficient mice

Respirology

(2005)

J.W. Card et al.

Cyclooxygenase-1 overexpression decreases Basal airway responsiveness but not allergic inflammation

J Immunol

(2006)

R.S. Peebles et al.

Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice

Am J Respir Crit Care Med

(2000)

R.S. Peebles et al.

Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice

Am J Respir Crit Care Med

(2002)

L. Swedin et al.

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Eur Respir J

(2009)

M.C. Liu et al.

Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma

Am Rev Respir Dis

(1990)

J.E. Fish et al.

Indomethacin modification of immediate-type immunologic airway responses in allergic asthmatic and non-asthmatic subjects: evidence for altered arachidonic acid metabolism in asthma

Am Rev Respir Dis

(1981)

J.G. Kirby et al.

Effect of indomethacin on allergen-induced asthmatic responses

J Appl Physiol

(1989)

L.J. Roberts et al.

Increased production of prostaglandin D2 in patients with systemic mastocytosis

N Engl J Med

(1980)

K. Tanaka et al.

Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets

J Immunol

(2000)

Y. Urade et al.

The major source of endogenous prostaglandin D2 production is likely antigen-presenting cells. Localization of glutathione-requiring prostaglandin D synthetase in histiocytes, dendritic, and Kupffer cells in various rat tissues

J Immunol

(1989)

K. Honda et al.

Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine

J Exp Med

(2003)

Y. Fujitani et al.

Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice

J Immunol

(2002)

H. Hammad et al.

Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1

J Immunol

(2003)

H. Hammad et al.

Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells

J Exp Med

(2007)

I. Spik et al.

Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse

J Immunol

(2005)

L. Uller et al.

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Respir Res

(2007)

J.J. Murray et al.

Release of prostaglandin D2 into human airways during acute antigen challenge

N Engl J Med

(1986)

R.M. Naclerio et al.

Mediator release after nasal airway challenge with allergen

Am Rev Respir Dis

(1983)

S.L. Johnston et al.

Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor

Eur Respir J

(1995)

T.R. Martin et al.

Pulmonary responses to bronchoconstrictor agonists in the mouse

J Appl Physiol

(1988)

N. Barnes et al.

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma

Clin Exp Allergy

(2012)

F. Horak et al.

The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial

Allergy

(2012)

D. Singh et al.

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Eur Respir J

(2013)

A. Straumann et al.

Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis

Allergy

(2013)

R.M. Breyer et al.

Prostanoid receptors: subtypes and signaling

Annu Rev Pharmacol Toxicol

(2001)

J.M. Hartney et al.

Prostaglandin E2 protects lower airways against bronchoconstriction

Am J Physiol Lung Cell Mol Physiol

(2006)

J.R. Sheller et al.

EP(2) receptor mediates bronchodilation by PGE(2) in mice

J Appl Physiol

(2000)

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: Disclaimers: Dr Boyce has received honoraria from Merck.

: Funding Sources: This work was supported by grants 53202 and A100306 from the National Institutes of Health.

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Basic Science for the Practicing ClinicianLipid mediators and allergic diseases

Abstract

Objective

Data Sources

Study Selections

Results

Conclusions

Introduction

Section snippets

Generation of Lipid Mediator Precursors

Overview of the Cyclooxygenase Pathway

PGD2 and Its Receptors, DP1 and DP2/Chemoattractant Homologous Molecule Expressed on TH2 Cells

Overview of the 5-LO Pathway

Cys-LTs and Their Receptors

Discussion

Conclusions

Biochim Biophys Acta

Prog Lipid Res

Prostaglandins Leukot Essent Fatty Acids

Adv Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Pulm Pharmacol Ther

Prostaglandins Leukot Essent Fatty Acids

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

Adv Immunol

J Biol Chem

Blood

Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation

Annu Rev Pharmacol Toxicol

Why there are two cyclooxygenase isozymes

J Clin Invest

Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic

FASEB J

Airway inflammation and responsiveness in prostaglandin H synthase–deficient mice exposed to bacterial lipopolysaccharide

Am J Respir Cell Mol Biol

Accentuated T helper type 2 airway response after allergen challenge in cyclooxygenase-1−/− but not cyclooxygenase-2−/− mice

Am J Respir Crit Care Med

Augmentation of allergic inflammation in the airways of cyclooxygenase-2–deficient mice

Respirology

Cyclooxygenase-1 overexpression decreases Basal airway responsiveness but not allergic inflammation

J Immunol

Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice

Am J Respir Crit Care Med

Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice

Am J Respir Crit Care Med

Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice

Eur Respir J

Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma

Am Rev Respir Dis

Indomethacin modification of immediate-type immunologic airway responses in allergic asthmatic and non-asthmatic subjects: evidence for altered arachidonic acid metabolism in asthma

Am Rev Respir Dis

Effect of indomethacin on allergen-induced asthmatic responses

J Appl Physiol

Increased production of prostaglandin D2 in patients with systemic mastocytosis

N Engl J Med

Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets

J Immunol

The major source of endogenous prostaglandin D2 production is likely antigen-presenting cells. Localization of glutathione-requiring prostaglandin D synthetase in histiocytes, dendritic, and Kupffer cells in various rat tissues

J Immunol

Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine

J Exp Med

Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice

J Immunol

Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1

J Immunol

Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells

J Exp Med

Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse

J Immunol

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Respir Res

Release of prostaglandin D2 into human airways during acute antigen challenge

N Engl J Med

Mediator release after nasal airway challenge with allergen

Basic Science for the Practicing Clinician
Lipid mediators and allergic diseases

PGD₂ and Its Receptors, DP₁ and DP₂/Chemoattractant Homologous Molecule Expressed on T_H2 Cells