Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling

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Abstract

A new paradigm for asthma pathogenesis is presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from a subject's susceptibility to components of the inhaled environment. An epithelial-mesenchymal trophic unit becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. Histamine, prostanoids, and cysteinyl leukotrienes (CysLTs) are potent contractile agonists of airway smooth muscle (ASM). The CysLTs appear to play a central role in regulating human ASM motor tone and phenotypic alterations, manifested as hypertrophy and hyperplasia in chronic severe asthma. The CysLTs augment growth factor–induced ASM mitogenesis through activation of CysLT receptors. Although they mediate their contractile effects by increasing phosphoinositide turnover and inducing increased cytosolic calcium, new data suggest that part of the contractile effect may be independent of calcium mobilization. Prostaglandin E2, the predominant eicosanoid product of the airway epithelium, is a potent inhibitor of mitogenesis, collagen synthesis, and mesenchymal cell chemotaxis and therefore can suppress inflammation and fibroblast activation. The capacity of the epithelium for CysLT synthesis is inversely related to its ability to make PGE2. The ASM is capable of expressing both leukotriene-synthesizing enzymes and CysLT receptors, and cytokines upregulate the receptor expression. This may be an explanation for the CysLTs promoting airway hyperresponsiveness in asthma. The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis. Evidence from a mouse model of asthma demonstrated that CysLT1 receptor antagonists inhibit the airway remodeling processes, including eosinophil trafficking to the lungs, eosinophil degranulation, TH2 cytokine release, mucus gland hyperplasia, mucus hypersecretion, smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis. (J Allergy Clin Immunol 2003;111:S18-36.)

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

. Cell stiffness responses to LTD4 (10-7 mol/L) (black bars) and bradykinin (10-6 mol/L) (white bars) of human ASM cells treated with IFN-γ (1000 U/mL for 24

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 remodeling in asthma

Airway wall thickening
Subepithelial fibrosis
Hyperplasia of mucus glands
Myofibroblasts
Smooth muscle
Vasculature
Airway thickening beneath the basement membrane occurs with collagen deposition and other

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).

. Anti-inflammatory and antiremodeling effects of LTRAs

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

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    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.

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