Eicosanoid Lipid Mediators in Fibrotic Lung Diseases: Ready for Prime Time?

doi:10.1378/chest.08-0306

Chest

Volume 133, Issue 6, June 2008, Pages 1442-1450

https://doi.org/10.1378/chest.08-0306 Get rights and content

Recognition of a pivotal role for eicosanoids in both normal and pathologic fibroproliferation is long overdue. These lipid mediators have the ability to regulate all cell types and nearly all pathways relevant to fibrotic lung disorders. Abnormal fibroproliferation is characterized by an excess of profibrotic leukotrienes and a deficiency of antifibrotic prostaglandins. The relevance of an eicosanoid imbalance is pertinent to diseases involving the parenchymal, airway, and vascular compartments of the lung, and is supported by studies conducted both in humans and animal models. Given the lack of effective alternatives, and the existing and emerging options for therapeutic targeting of eicosanoids, such treatments are ready for prime time.

Section snippets

Eicosanoids: Synthesis and Cellular Effects

Eicosanoids are a group of lipid mediators derived from the 20-carbon fatty acid arachidonic acid (eicosa is Greek for “20”). After release from membrane phospholipids by cytosolic phospholipase A₂ (Fig 1), arachidonate is further metabolized by the 5-lipoxygenase (5-LO) pathway into LTs or by the cyclooxygenase (COX)-1/COX-2 pathway into PGs.³ LTs include both LTB₄ and the cysteinyl LTs (cysLTs) C₄, D₄, and E₄, and are synthesized mainly by leukocytes. PGs, including PGE₂, PGI₂, PGD₂, PGF₂α,

Conclusion

Eicosanoids have been shown to influence nearly all of the pathobiological aspects of pulmonary fibroproliferation. They can directly influence inflammatory cells, alveolar epithelial cells, and mesenchymal cells, and exert indirect effects by modulating a multitude of peptide mediators, chemokines, and other relevant pathways. Accumulating evidence supports a paradigm of eicosanoid imbalance in which human fibrotic lung disorders are characterized by an excess of profibrotic LTs, a deficiency

References (56)

A Fine et al.
The differential effect of prostaglandin E2 on transforming growth factor-β and insulin-induced collagen formation in lung fibroblasts
J Biol Chem
(1989)
BJ Baum et al.
Effect of cyclic AMP on the intracellular degradation of newly synthesized collagen
J Biol Chem
(1980)
RJ Hodges et al.
Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production
Am J Pathol
(2004)
CB Keerthisingam et al.
Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-β in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice
Am J Pathol
(2001)
AJ Wardlaw et al.
Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases
J Allergy Clin Immunol
(1989)
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)
MM Kelly et al.
Montelukast treatment attenuates the increase in myofibroblasts following low-dose allergen challenge
Chest
(2006)
M Pierzchalska et al.
Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients, with special reference to aspirin-induced asthma
J Allergy Clin Immunol
(2003)
T Izumo et al.
Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in mice
Life Sci
(2007)
DA Kujubu et al.
Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene
J Biol Chem
(1992)

M Selman et al.

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

(2001)

American Thoracic Society et al.

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001

Am J Respir Crit Care Med

(2002)

CD Funk

Prostaglandins and leukotrienes: advances in eicosanoid biology

Science

(2001)

RP Charbeneau et al.

Eicosanoids: mediators and therapeutic targets in fibrotic lung disease

Clin Sci (Lond)

(2005)

M Peters-Golden et al.

Leukotrienes

N Engl J Med

(2007)

Y Bosse et al.

Leukotriene D4-induced, epithelial cell-derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation

Clin Exp Allergy

(2008)

B Uzonyi et al.

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Proc Natl Acad Sci U S A

(2006)

SH Phan et al.

Leukotriene C4 binds to rat lung fibroblasts and stimulates collagen synthesis

Adv Prostaglandin Thromboxane Res

(1987)

KM Vannella et al.

Cysteinyl leukotrienes are autocrine and paracrine regulators of fibrocyte function

J Immunol

(2007)

RA Armstrong

Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils

Br J Pharmacol

(1995)

U Savla et al.

Prostaglandin E(2) regulates wound closure in airway epithelium

Am J Physiol Lung Cell Mol Physiol

(2001)

ES White et al.

Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity

Am J Respir Cell Mol Biol

(2005)

J Choung et al.

Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts

J Cell Biochem

(1998)

CM Skold et al.

Glucocorticoids augment fibroblast-mediated contraction of collagen gels by inhibition of endogenous PGE production

Proc Assoc Am Physicians

(1999)

PE Thomas et al.

PGE(2) inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling

Am J Physiol Lung Cell Mol Physiol

(2007)

A Zhang et al.

Prostaglandin E2 is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor

Am J Physiol Renal Physiol

(2006)

M Peters-Golden et al.

Protection from pulmonary fibrosis in leukotriene-deficient mice

Am J Respir Crit Care Med

(2002)

TC Beller et al.

Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis

Proc Natl Acad Sci U S A

(2004)

Cited by (60)

Interaction Between Epithelial and Mesenchymal Cells in Interstitial Lung Disease
2021, Encyclopedia of Respiratory Medicine, Second Edition
Alveolar epithelial cell dysfunction plays a central role in the pathogenesis of idiopathic pulmonary fibrosis, the prototypical fibrotic interstitial lung disease. The current model of IPF is that dysfunction of the alveolar epithelium leads to mesenchymal cell activation and extracellular matrix remodeling, leading to a feed-forward pro-fibrotic process. Interactions between epithelial and mesenchymal cells in fibrotic interstitial lung disease are reviewed here.
Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue
2020, Journal of Allergy and Clinical Immunology
Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E₂ exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE₂ metabolism under the control of TGF-β and microRNA 218.
We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue.
In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis.
We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE₂ levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE₂ that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro.
These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis
2017, American Journal of Transplantation
Fibrosis after solid organ transplantation is considered an irreversible process and remains the major cause of graft dysfunction and death with limited therapies. This remodeling is characterized by aberrant accumulation of contractile myofibroblasts that deposit excessive extracellular matrix (ECM) and increase tissue stiffness. Studies demonstrate, however, that a stiff ECM itself promotes fibroblast-to-myofibroblast differentiation, stimulating further ECM production. This creates a positive feedback loop that perpetuates fibrosis. We hypothesized that simultaneously targeting myofibroblast contractility with relaxin and ECM stiffness with lysyl oxidase inhibitors could break the feedback loop, reversing established fibrosis. To test this, we used the orthotopic tracheal transplantation (OTT) mouse model, which develops robust fibrotic airway remodeling. Mice with established fibrosis were treated with saline, mono-, or combination therapies. Although monotherapies had no effect, combining these agents decreased collagen deposition and promoted re-epithelialization of remodeled airways. Relaxin inhibited myofibroblast differentiation and contraction in a matrix-stiffness–dependent manner through prostaglandin E₂ (PGE₂). Furthermore, the effect of combination therapy was lost in PGE₂ receptor knockout and PGE₂-inhibited OTT mice. This study revealed the important synergistic roles of cellular contractility and tissue stiffness in the maintenance of fibrotic tissue and suggests a new therapeutic principle for fibrosis.
Repair Mechanisms in Oxidant-Driven Chronic Inflammatory Disease
2016, American Journal of Pathology
Citation Excerpt :
In the lung, COX-derived PGE2 plays a crucial role as a potent vasodilator that induces its effects via its actions on two PGE2 receptors, EP2 and EP4 (Figure 2).40–42 PGE2 secretion also suppresses lung inflammation, immune responses, and fibrotic processes on the basis of its ability to limit continuous infiltration of inflammatory cells, their consequent activation, and proinflammatory mediator release of LTs from the 5-LOX pathway that can contribute to vascular remodeling and tissue damage.72,73 Thus, recent evidence supports a critical balance between PGs and LTs for maintaining homeostatic conditions in airways and all lung compartments (Figure 2).
The interplay that governs chronic diseases through pathways specifically associated with chronic inflammation remains undefined. Many metabolic events have been identified during the injury and repair process. Nonetheless, the cellular events that control the pathogenesis of inflammation-induced disease have not been fully characterized. We and others reason that chronic inflammatory diseases associated with a cascade of complex network mediators, such as nitric oxide, arachidonic acid metabolites, cytokines, and reactive oxygen species, play a significant role in the governance of alterations in homeostasis, oxidative stress, and thromboatherosclerosis. In this context, we discuss lipid mediators associated with the maintenance of health, including the specialized proresolving mediators that help drive cellular repair. Emphasis is placed on the pathophysiology of chronic metabolic insults involving both the airways and the cardiovascular system during oxidant-driven inflammatory disease. In this review, we highlight new pathways of inquiry that show promise for the identification of those metabolic targets that can improve therapy for chronic inflammation.
Prostaglandin E<inf>2</inf> possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts
2016, Prostaglandins Leukotrienes and Essential Fatty Acids
We studied the role of PGE₂, its biosynthetic enzymes and its receptors, in regulating the functions of lung fibroblasts through the production of Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) in COPD subjects.
Lung fibroblasts from Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE₂, VEGF, and IL-8 measured in supernatants by ELISA. COX-1/COX-2 and EP receptors expression were assessed by western blot and by RT-PCR. Release of VEGF and IL-8 by human fetal lung fibroblasts (HFL-1; lung, diploid, human) was evaluated under different conditions.
PGE₂, VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. Low concentrations of synthetic PGE₂ increased the release of VEGF in HFL-1, but higher concentrations were needed to induce the release of IL-8. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist.
In the airways of COPD subjects, fibroblast-derived PGE₂ may regulate angiogenesis and inflammation through the production of VEGF and IL-8 respectively, suggesting that the increase in expression of COX-2, EP2 and EP4 observed in COPD fibroblasts may contribute to steering the role of PGE₂ from homeostatic to pro-inflammatory.
Prostanoids in asthma and COPD actions, dysregulation, and th erapeutic opportunities
2015, Chest
Citation Excerpt :
Their synthesis entails hydrolysis of arachidonic acid from membrane phospholipids by phospholipase A2, its oxygenation by constitutive cyclooxygenase (COX)-1 and inducible COX-2 isoforms, and isomerization by specific terminal synthases (Fig 1). PGE2 is produced by virtually all lung cell types, but the most abundant sources are epithelial cells, fibroblasts, and macrophages.3 The major source of PGI2 is endothelial cells.4
Pathophysiologic gaps in the actions of currently available treatments for asthma and COPD include neutrophilic inflammation, airway remodeling, and alveolar destruction. All of these processes can be modulated by cyclic adenosine monophosphate-elevating prostaglandins E₂ and I₂ (also known as prostacyclin). These prostanoids have long been known to elicit bronchodilation and to protect against bronchoconstriction provoked by a variety of stimuli. Much less well known is their capacity to inhibit inflammatory responses involving activation of lymphocytes, eosinophils, and neutrophils, as well as to attenuate epithelial injury and mesenchymal cell activation. This profile of actions identifies prostanoids as attractive candidates for exogenous administration in asthma. By contrast, excessive prostanoid production and signaling might contribute to both the increased susceptibility to infections that drive COPD exacerbations and the inadequate alveolar repair that characterizes emphysema. Inhibition of endogenous prostanoid synthesis or signaling, thus, has therapeutic potential for these types of patients. By virtue of their pleiotropic capacity to modulate numerous pathophysiologic processes relevant to the expression and natural history of airway diseases, prostanoids emerge as attractive targets for therapeutic manipulation.

View all citing articles on Scopus

This work was performed at the University of Michigan and funded by National Institutes of Health grant P50 HL56402 from the National Heart, Lung, and Blood Institute. Dr. Huang was supported by National Institutes of Health grant T32 HL07749.

Reproduction of this article is prohibited without written permission from the American College of chest Physicians (www.chestjournal.org/misc/rerints.shtml).

¹: Dr. Huang has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Dr. Peters-Golden has received consultant fees and lecture honoraria from Merck and Critical Therapeutics.

View full text

Chest

Translating Basic Research into Clinical PracticeEicosanoid Lipid Mediators in Fibrotic Lung Diseases: Ready for Prime Time?

Section snippets

Eicosanoids: Synthesis and Cellular Effects

Conclusion

J Biol Chem

J Biol Chem

Am J Pathol

Am J Pathol

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Life Sci

J Biol Chem

Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy

Ann Intern Med

Am J Respir Crit Care Med

Prostaglandins and leukotrienes: advances in eicosanoid biology

Science

Eicosanoids: mediators and therapeutic targets in fibrotic lung disease

Clin Sci (Lond)

Leukotrienes

N Engl J Med

Leukotriene D4-induced, epithelial cell-derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation

Clin Exp Allergy

Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells

Proc Natl Acad Sci U S A

Leukotriene C4 binds to rat lung fibroblasts and stimulates collagen synthesis

Adv Prostaglandin Thromboxane Res

Cysteinyl leukotrienes are autocrine and paracrine regulators of fibrocyte function

J Immunol

Investigation of the inhibitory effects of PGE2 and selective EP agonists on chemotaxis of human neutrophils

Br J Pharmacol

Prostaglandin E(2) regulates wound closure in airway epithelium

Am J Physiol Lung Cell Mol Physiol

Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity

Am J Respir Cell Mol Biol

Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts

J Cell Biochem

Glucocorticoids augment fibroblast-mediated contraction of collagen gels by inhibition of endogenous PGE production

Proc Assoc Am Physicians

PGE(2) inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling

Am J Physiol Lung Cell Mol Physiol

Prostaglandin E2 is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor

Am J Physiol Renal Physiol

Protection from pulmonary fibrosis in leukotriene-deficient mice

Am J Respir Crit Care Med

Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis

Proc Natl Acad Sci U S A

Translating Basic Research into Clinical Practice
Eicosanoid Lipid Mediators in Fibrotic Lung Diseases: Ready for Prime Time?