Journal of Allergy and Clinical Immunology
Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling☆
Section snippets
Difficulties in linking atopy and asthma in a linear model for asthma
Atopy is one of the strongest risk factors associated with asthma, but it is difficult to explain asthma purely in terms of lower respiratory allergy. Although up to 50% of a population has atopy, less than 10% actually have persistent asthma, and the level of exposure in early life is not associated with the development of asthma in those who become sensitized to aeroallergens.2 In countries that have not adopted a Western lifestyle (eg, Albania), the prevalence of atopy is similar to that in
Increased epithelial injury and disordered repair in asthma
The normal differentiated bronchial epithelium is a stratified structure consisting of a columnar layer comprising ciliated and secretory cells that are supported by basal cells. This polarized structure is the physical barrier protecting the internal milieu of the lungs from inhaled pollutants, infectious agents, and other particulate matter. Under normal conditions, the bronchial epithelium is engaged actively in defense of the airways by secreting mucus and many specific and nonspecific
Cysteinyl leukotrienes, fibroblasts, remodeling, and pulmonary fibrosis
Airway remodeling refers to the structural changes that can occur in asthma that may be associated with irreversible airflow obstruction. These alterations include hyperplasia of smooth muscle cells and fibroblasts as well as deposition of matrix proteins such as collagen in the airway wall. First, TGF-β, implicated in the differentiation of fibroblasts to myofibroblasts, also increases CysLT synthesis by macrophages.35, 36 Second, CysLTs increase the proliferative response of lung fibroblasts
Epithelial-derived prostaglandin E2: Effects on inflammation/remodeling and influence on leukotriene biosynthesis
The epithelial cell–fibroblast dyad has recently been highlighted as being of central importance in the development of both pulmonary fibrosis39 and airway remodeling.45 The current paradigm posits that under normal conditions, epithelial cells suppress fibroblast proliferation and collagen synthesis and that fibrosis is favored by conditions that result in a loss of this usual epithelial suppression or a state of epithelial activation of fibroblast function. The predominant eicosanoid product
Leukotriene receptor expression on airway smooth muscle cells
Evidence suggests that CysLTs, especially LTD4, play an important role in the asthmatic bronchoconstriction. For example, leukotriene modifier drugs that block the action of LTD4, either by inhibiting its synthesis or by abrogating its ability to bind to the CysLT receptor, are efficacious in the treatment of asthmatic patients.69 Despite the characterization of the structure and the sequencing of the CysLT receptors, little is known concerning the cellular and molecular mechanisms that alter
Cytokine influence
According to a recent study, interferon (IFN)-γ enhances the expression of the CysLT1 receptor and increases contractile responses to LTD4 in human ASM cells.70 When measured by flow cytometry, the upregulation of CysLT1 was associated with an increase in steady-state mRNA levels of the CysLT1 and CysLT2 genes. An upregulation of the CysLT1 receptor and an enhanced sensitivity to LTD4 was also observed in response to IL-5 in HL-60 cells.49 Furthermore, in untreated eosinophils, the CysLT1 mRNA
Viral infections
The ability of IFN-γ to modulate CysLT1 receptor expression and function in human ASM cells has important implications for airway diseases such as asthma. First, both CysLT1 receptor protein and mRNA are expressed in vivo in ASM.71 Second, IFN-γ levels within the airways are dramatically increased in asthmatic persons72, 73 and after viral infections.69 The primary components of the IFN-γ signaling system, STAT-1, and STAT-1–dependent genes, have been activated in the airway epithelium of
Smooth muscle and cell stiffness
Interferon-γ has been shown to enhance LTD4-induced changes in human ASM cell stiffness. Measured by magnetic twisting cytometry, cell stiffness can be used as a proxy for force generation in ASM cells.79, 80 It is likely that the observed changes in cell stiffness are caused by increases in CysLT1 expression with IFN-γ treatment (Fig 6).70
Modulators of asm cell proliferation
Although the leukotrienes mimic many asthma features, little is known about the influence of the leukotrienes on ASM proliferation. Both LTB4 and LTD4 augmented ASM proliferation in vitro when combined with EGF or IGF,83 and growth factors play a crucial role in regulating cell proliferation and survival.84, 85 In a model of asthma, repeated challenge with ovalbumin (OVA) in OVA-sensitized rats produced increased ASM mass in airways larger than 2 mm in diameter, which was partially inhibited by
Remodeling and airflow obstruction
Persistent allergic airway inflammation in asthma is accompanied by airway remodeling changes, including hyperplasia of airway mucus glands, myofibroblasts, smooth muscle and vasculature, and the thickening of the airway wall with subepithelial fibrosis (Table I).88, 89
Airway wall thickening Subepithelial fibrosis Hyperplasia of mucus glands Myofibroblasts Smooth muscle Vasculature
Variable asthma phenotypes
Asthmatic patients have shown significant variability in cellular inflammation and structural changes, suggesting that distinct immunologic/pathologic phenotypes may exist.95 Patients with mild persistent asthma have shown features of airway remodeling in bronchial biopsy specimens, including thickening of the subepithelial lamina reticularis.96 Most patients with mild persistent asthma, however, do not have progressive airflow limitation characteristic of severe asthma. A 15-year longitudinal
Effects of leukotriene modifiers on inflammation and remodeling
A number of leukotriene modifiers have been introduced as alternative or additional anti-inflammatory agents (Table III).
CysLT1 receptor antagonists block key features of allergic airway inflammation and remodeling including Eosinophil trafficking to the lungs and eosinophil degranulation Pulmonary TH2 cytokine release Airway goblet cell hyperplasia and mucus hypersecretion Airway smooth muscle hyperplasia Collagen deposition and fibrosis in the
Conclusions
A new paradigm for asthma pathogenesis was presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from the susceptibility of the bronchial epithelium to components of the inhaled environment. At this environment-gene interface, an EMTU becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. This paradigm also suggests that remodeling and
References (127)
Genetic and environmental interactions in allergy and asthma
J Allergy Clin Immunol
(1999)- et al.
Early exposure to house-dust mite and cat allergens and development of childhood asthma: A cohort study: Multicentre Allergy Study Group
Lancet
(2000) - et al.
Effects of interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness and the late asthmatic response
Lancet
(2000) - et al.
The molecular basis of lung morphogenesis
Mech Dev
(2000) - et al.
Epithelial-mesenchymal intereactions in the pathogenesis of asthma
J Allergy Clin Immunol
(2000) - et al.
Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium
J Allergy Clin Immunol
(2001) - et al.
Involvement of calcium in macrophage leukotriene release during experimental cirrhosis
Hepatology
(1996) - et al.
The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts
J Biol Chem
(1982) - et al.
Regulation of oxygen radical release from murine peritoneal macrophages by pharmacologic doses of PGE2
Free Radic Biol Med
(1987) - et al.
Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression
J Biol Chem
(1988)
Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells
J Biol Chem
Leukotriene receptors
J Lipid Mediat Cell Signal
Characterization of the human cysteinyl leukotriene 2 receptor
J Biol Chem
Pharmacology of leukotriene receptor antagonists: More than inhibitors of bronchoconstriction
Chest
A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis
J Biol Chem
Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack
Chest
Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine
Chest
Fibroblast-matrix interactions in wound healing and fibrosis
Matrix Biol
Pathophysiology of severe asthma
J Allergy Clin Immunol
Remodeling in near-fatal asthma [abstract]
J Allergy Clin Immunol
Is asthma really due to a polarized T cell response toward a helper T cell type 2 phenotype?
Am J Respir Crit Care Med
Results of a phase 1 trial with SCH 55700, a humanised anti-IL-5 antibody in severe persistent asthma [abstract]
Am J Respir Crit Care Med
Genetic and environmental influence on asthma: A population-based study of 11,688 Danish twin pairs
Eur Respir J
Oxidative stress and regulation of glutathione in lung inflammation
Eur Respir J
Diet, infection and wheezy illness: Lessons from adults
Pediatr Allergy Immunol
The role of viral and atypical bacterial pathogens in asthma pathogenesis
Pediatr Pulmonol Suppl
Airway hyperresponsiveness: Exploration of mechanisms using a dynamic, computer based model [abstract]
Am J Respir Crit Care Med
A 15-year follow-up study of ventilatory function in adults with asthma
N Engl J Med
Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma
Thorax
Eosinophilic inflammation in the bronchial mucosa of children with bronchial asthma [abstract]
Eur Respir J
Long-term effects of budesonide or nedocromil in children with asthma: The Childhood Asthma Management Program Research Group
N Engl J Med
Mast-cell infiltration of airway smooth muscle in asthma
N Engl J Med
Cytokines in asthma
Thorax
Epithelial desquamation in asthma: Artifact or pathology?
Am J Respir Crit Care Med
Involvement of the epidermal growth factor receptor in epithelial repair in asthma
FASEB J
Increased sensitivity of asthmatic bronchial epithelial cells to oxidant-induced injury [abstract]
Am J Respir Crit Care Med
Myofibroblasts and subepithelial fibrosis in bronchial asthma
Am J Respir Cell Mol Biol
Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: An in vitro co-culture model of airway remodeling in asthma
Lab Invest
Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma
Clin Exp Allergy
The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma
Am J Respir Cell Mol Biol
Asymptomatic airway hyperresponsiveness: Relationships with airway inflammation and remodelling
Eur Respir J
Lung development and early origins of respiratory illness
Br Med Bull
Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production
J Clin Invest
Co-operative effects of Th-2 cytokines and allergen on normal and asthmatic bronchial epithelial cells
J Immunol
Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells
Am J Physiol
Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: Differential sensitivity to cysteinyl leukotriene receptor antagonists
Am J Respir Cell Mol Biol
Expression and regulation of leukotriene pathway enzymes in human airway smooth muscle cells [abstract]
Am J Respir Crit Care Med
The expression of leukotriene pathway enzymes in human bronchial epithelial cells [abstract]
Eur Respir J
Transforming growth factor beta upregulates 5-lipoxygenase activity during myeloid cell maturation
Proc Natl Acad Sci U S A
TGF-beta increases leukotriene C4 synthase expression in the monocyte-like cell line, THP-1
J Immunol
Cited by (288)
Multifocal bronchial stenosis and extensive lobar atelectasis as a rare radiologic feature of severe eosinophilic asthma
2023, Journal of Allergy and Clinical Immunology: In PracticeSingle-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission
2022, Journal of Allergy and Clinical ImmunologyNovel potent benzimidazole-based microsomal prostaglandin E<inf>2</inf> synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C<inf>4</inf> synthase
2022, European Journal of Medicinal ChemistryNovel Immunomodulatory Therapies for Respiratory Pathologies
2022, Comprehensive PharmacologyTherapeutic targets in lung tissue remodelling and fibrosis
2021, Pharmacology and Therapeutics
- ☆
Reprint requests: Stephen T. Holgate, MD, DSc, University Medicine, Level D, Centre Block, Mail Point 810, Southampton General Hospital, Temona Road, Southampton SO16 6YD, United Kingdom.