Lipid metabolites as regulators of airway smooth muscle function

doi:10.1016/j.pupt.2008.12.003

Pulmonary Pharmacology & Therapeutics

Volume 22, Issue 5, October 2009, Pages 426-435

https://doi.org/10.1016/j.pupt.2008.12.003 Get rights and content

Abstract

Compelling evidence identifies airway smooth muscle (ASM) not only as a target but also a cellular source for a diverse range of mediators underlying the processes of airway narrowing and airway hyperresponsiveness in diseases such as asthma. These include the growing family of plasma membrane phospholipid-derived polyunsaturated fatty acids broadly characterised by the prostaglandins, leukotrienes, lipoxins, isoprostanes and lysophospholipids. In this review, we describe the enzymatic and non-enzymatic biosynthetic pathways of these lipid mediators and how these are influenced by drug treatment, oxidative stress and airways disease. Additionally, we outline their cognate receptors, many of which are expressed by ASM. We describe potential deleterious and protective roles for these lipid mediators in airway inflammatory and remodelling processes by describing their effects on diverse functions of ASM in asthma that have the potential to contribute to asthma pathogenesis and symptoms. These functions include contractile tone development, cytokine and extracellular matrix production, and cellular proliferation and migration.

Introduction

For many years, lipids were considered to be solely of dietary or structural importance. This view changed dramatically in the 1970s and 1980s with the discovery of the prostaglandins (PGs), the first lipid-derived intercellular mediators. It is now known that arachidonic acid is also the initial substrate for other important lipid-derived mediators including leukotrienes (LTs) and lipoxins (LXs). These mediators are all formed subsequent to the hydrolytic action of phospholipase A₂ (PLA₂) on the cellular phospholipids to release arachidonic acid (Fig. 1). Additionally, 8-isoprostanes can be produced when arachidonic acid undergoes non-enzymatic peroxidation by free radicals and reactive oxygen species (ROS), while in its free form or when esterified to membrane phospholipids (Fig. 1). PLA₂ can also catalyze the hydrolysis of cellular phospholipids to produce the lysophospholipids, another class of lipid mediators which incorporate lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). PGs, LTs, LXs, LPA and S1P, as well as others, are collectively referred to as lipid mediators. In this review we focus on the synthesis of these lipid mediators as well as expression of their cognate receptors with particular reference to airway smooth muscle (ASM). By describing their reported effects on ASM tone, cytokine and extracellular matrix (ECM) production, proliferation and migration, this review provides insight into the potential influence of these lipid mediators on both the contractile and synthetic functions of ASM in airways disease.

Section snippets

Prostanoids

Prostanoids are a class of lipid mediators encompassing the prostaglandins PGD₂, PGE₂, PGF_2α and PGI₂ (also known as prostacyclin) and thromboxane A₂ (TXA₂). They are key mediators and modulators of responses in both inflammatory and structural cells in the lung [1], with PGE₂ being the major prostanoid produced by ASM [2], [3]. Prostanoids are generated from arachidonic acid, which is released from phospholipid cell membranes by the action of PLA₂ and then converted to prostanoids via the

Effects on ASM contraction

The high local levels of lipid mediators in the lower respiratory tract [62] have the potential to mediate the complex effects on airway tone, either by acting directly on ASM or indirectly modulating neurally-mediated cholinergic contraction. Complete characterisation of the effects of a single mediator may be difficult, since it may elicit opposing effects on airway tone through non-specific activation of multiple receptors expressed on ASM and pre-synaptic nerve terminals (Table 1), and

Effects on ASM synthetic function

As outlined above, lipid mediators can regulate ASM contractile responses either directly or indirectly. Additionally, they may also modulate non-contractile or synthetic functions of ASM including the production of inflammatory mediators, cellular migration and proliferation. Alterations in ECM protein production by ASM in response to lipid mediators are also of interest, since the surrounding matrix has the potential to influence multiple ASM functions implicated in asthma pathophysiology

Conclusion

Lipid mediators, including the prostaglandins, leukotrienes, isoprostanes and the lysophospholipids S1P and LPA, have diverse effects on ASM function. Their enzymatic and non-enzymatic synthetic profile varies under physiological and pathological conditions, influenced by drug treatment, oxidative stress and airways disease. Selective and non-selective activation of prostanoid, leukotriene and lysophospholipid receptors by these mediators may regulate airway contractile responses directly and

Acknowledgements

Jane E. Ward was supported by National Health and Medical Research Council [Grant 509239] and the Asthma Foundation of Victoria. The authors would also like to thank Astra-Zeneca for sponsorship and the travel grants to attend the Sixth International Young Investigators' Symposium on Smooth Muscle in Sydney, Australia, November 2007.

References (134)

S. Rolin et al.
Prostanoids as pharmacological targets in COPD and asthma
Eur J Pharmacol
(2006)
M.A. Carey et al.
Cyclooxygenase enzymes in allergic inflammation and asthma
Prostaglandins Leukot Essent Fatty Acids
(2003)
H. Abe et al.
Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family
Gene
(1999)
X. Norel et al.
Vasoconstriction induced by activation of EP1 and EP3 receptors in human lung: effects of ONO-AE-248, ONO-DI-004, ONO-8711 or ONO-8713
Prostaglandins Other Lipid Mediat
(2004)
R.B. Penn et al.
Arrestin specificity for G protein-coupled receptors in human airway smooth muscle
J Biol Chem
(2001)
D. Oliva et al.
PGI2-receptors and molecular mechanisms in platelets and vasculature: state of the art
Pharmacol Res Commun
(1987)
M.K. Raychowdhury et al.
Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor
J Biol Chem
(1994)
V. Capra et al.
Thromboxane prostanoid receptor in human airway smooth muscle cells: a relevant role in proliferation
Eur J Pharmacol
(2003)
C.E. Heise et al.
Characterization of the human cysteinyl leukotriene 2 receptor
J Biol Chem
(2000)
J.D. Morrow et al.
Noncyclooxygenase oxidative formation of a series of novel prostaglandins: analytical ramifications for measurement of eicosanoids
Anal Biochem
(1990)

J.D. Morrow et al.

Evidence that the F2-isoprostane, 8-epi-prostaglandin F2 alpha, is formed in vivo

Biochim Biophys Acta

(1994)

J. Belik et al.

Peroxynitrite inhibits relaxation and induces pulmonary artery muscle contraction in the newborn rat

Free Radic Biol Med

(2004)

C.M. Hart et al.

Role of 8-epi PGF2alpha, 8-isoprostane, in H₂O₂-induced derangements of pulmonary artery endothelial cell barrier function

Prostaglandins Leukot Essent Fatty Acids

(1998)

A.W. Longmire et al.

Actions of the E2-isoprostane, 8-ISO-PGE2, on the platelet thromboxane/endoperoxide receptor in humans and rats: additional evidence for the existence of a unique isoprostane receptor

Prostaglandins

(1994)

H. Rosen et al.

Sphingosine 1-phosphate pathway therapeutics: a lipid ligand–receptor paradigm

Curr Opin Chem Biol

(2003)

K. Hama et al.

Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1

J Biol Chem

(2004)

K. Nakamura et al.

Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation

Clin Chim Acta

(2008)

I. Ishii et al.

Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3

J Biol Chem

(2001)

M.H. Graler et al.

EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue

Genomics

(1998)

D.S. Im et al.

Characterization of a novel sphingosine 1-phosphate receptor, Edg-8

J Biol Chem

(2000)

K. Terai et al.

Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS

Neuroscience

(2003)

S. An et al.

Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid

J Biol Chem

(1998)

K. Bandoh et al.

Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid

J Biol Chem

(1999)

C. Vancheri et al.

The lung as a privileged site for the beneficial actions of PGE2

Trends Immunol

(2004)

J. Tamaoki et al.

Relaxation and inhibition of contractile response to electrical field stimulation by Beraprost sodium in canine airway smooth muscle

Prostaglandins

(1993)

K.G. Mugridge et al.

Prostacyclin modulates the responses to leukotrienes C4 and D4 of guinea-pig airway smooth muscle

Eur J Pharmacol

(1984)

C.D. Funk et al.

Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype

J Biol Chem

(1993)

W.K. Sonnenburg et al.

A prostaglandin E receptor coupled to a pertussis toxin-sensitive guanine nucleotide regulatory protein in rabbit cortical collecting tubule cells

J Biol Chem

(1990)

M. McKenniff et al.

Characterisation of receptors mediating the contractile effects of prostanoids in guinea-pig and human airways

Eur J Pharmacol

(1988)

C.L. Armour et al.

Characterization of contractile prostanoid receptors on human airway smooth muscle

Eur J Pharmacol

(1989)

S.R. Findlay et al.

Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma

J Allergy Clin Immunol

(1992)

K. Espinosa et al.

CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4

J Allergy Clin Immunol

(2003)

J.E. Thorpe et al.

Leukotriene B4 potentiates airway muscle responsiveness in vivo and in vitro

Prostaglandins

(1986)

P.B. Helli et al.

The bronchodilators 8-iso-prostaglandin E2 and prostaglandin E2 induce K+ current suppression via thromboxane A2 receptors in porcine tracheal smooth muscle

Eur J Pharmacol

(2004)

M.G. Belvisi et al.

Induction of cyclooxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type

Br J Pharmacol

(1997)

F. Delamere et al.

Production of PGE2 by bovine cultured airway smooth muscle cells and its inhibition by cyclooxygenase inhibitors

Br J Pharmacol

(1994)

J.R. Vane

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nat New Biol

(1971)

R.G. Kurumbail et al.

Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

Nature

(1996)

L. Pang et al.

The COX-1/COX-2 balance in asthma

Clin Exp Allergy

(1998)

P. Demoly et al.

Prostaglandin H synthase 1 and 2 immunoreactivities in the bronchial mucosa of asthmatics

Am J Respir Crit Care Med

(1997)

L. Ermert et al.

Cyclooxygenase isoenzyme localization and mRNA expression in rat lungs

Am J Respir Cell Mol Biol

(1998)

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)

R.M. Pascual et al.

Regulatory features of interleukin-1beta-mediated prostaglandin E2 synthesis in airway smooth muscle

Am J Physiol Lung Cell Mol Physiol

(2006)

R.A. Coleman et al.

International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes

Pharmacol Rev

(1994)

T. Matsuoka et al.

Prostaglandin D2 as a mediator of allergic asthma

Science

(2000)

K. Parameswaran et al.

Modulation of human airway smooth muscle migration by lipid mediators and Th-2 cytokines

Am J Respir Cell Mol Biol

(2007)

S. Narumiya et al.

Prostanoid receptors: structures, properties, and functions

Physiol Rev

(1999)

S.L. Tilley et al.

Receptors and pathways mediating the effects of prostaglandin E2 on airway tone

Am J Physiol Lung Cell Mol Physiol

(2003)

M.J. Ratcliffe et al.

Activation of E-prostanoid4 and E-prostanoid2 receptors inhibits TNF-alpha release from human alveolar macrophages

Eur Respir J

(2007)

T. Matsuoka et al.

Prostaglandin receptor signaling in disease

ScientificWorldJournal

(2007)

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Lipid metabolites as regulators of airway smooth muscle function

Abstract

Introduction

Section snippets

Prostanoids

Effects on ASM contraction

Effects on ASM synthetic function

Conclusion

Acknowledgements

Eur J Pharmacol

Prostaglandins Leukot Essent Fatty Acids

Gene

Prostaglandins Other Lipid Mediat

J Biol Chem

Pharmacol Res Commun

J Biol Chem

Eur J Pharmacol

J Biol Chem

Anal Biochem

Biochim Biophys Acta

Free Radic Biol Med

Prostaglandins Leukot Essent Fatty Acids

Prostaglandins

Curr Opin Chem Biol

J Biol Chem

Clin Chim Acta

J Biol Chem

Genomics

J Biol Chem

Neuroscience

J Biol Chem

J Biol Chem

Trends Immunol

Prostaglandins

Eur J Pharmacol

J Biol Chem

J Biol Chem

Eur J Pharmacol

Eur J Pharmacol

J Allergy Clin Immunol

J Allergy Clin Immunol

Prostaglandins

Eur J Pharmacol

Induction of cyclooxygenase-2 by cytokines in human cultured airway smooth muscle cells: novel inflammatory role of this cell type

Br J Pharmacol

Production of PGE2 by bovine cultured airway smooth muscle cells and its inhibition by cyclooxygenase inhibitors

Br J Pharmacol

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nat New Biol

Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

Nature

The COX-1/COX-2 balance in asthma

Clin Exp Allergy

Prostaglandin H synthase 1 and 2 immunoreactivities in the bronchial mucosa of asthmatics

Am J Respir Crit Care Med

Cyclooxygenase isoenzyme localization and mRNA expression in rat lungs

Am J Respir Cell Mol Biol

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

Am J Respir Crit Care Med

Regulatory features of interleukin-1beta-mediated prostaglandin E2 synthesis in airway smooth muscle

Am J Physiol Lung Cell Mol Physiol

International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes

Pharmacol Rev

Prostaglandin D2 as a mediator of allergic asthma

Science

Modulation of human airway smooth muscle migration by lipid mediators and Th-2 cytokines

Am J Respir Cell Mol Biol

Prostanoid receptors: structures, properties, and functions

Physiol Rev

Receptors and pathways mediating the effects of prostaglandin E2 on airway tone

Am J Physiol Lung Cell Mol Physiol

Activation of E-prostanoid4 and E-prostanoid2 receptors inhibits TNF-alpha release from human alveolar macrophages

Eur Respir J

Prostaglandin receptor signaling in disease

ScientificWorldJournal