Leukotriene Synthesis Inhibitors Versus Antagonists: The Pros and Cons John W. Steinke, PhD, and Jeffrey A. Culp, MD
Corresponding author John W. Steinke, PhD Asthma and Allergic Disease Center, Beirne Carter Center for Immunology Research, University of Virginia Health System, Charlottesville, VA 22908-1355, USA. E-mail:
[email protected] Current Allergy and Asthma Reports 2007, 7:126 –133 Current Medicine Group LLC ISSN 1529-7322 Copyright © 2007 by Current Medicine Group LLC
It has been recognized for many years that leukotrienes play an important role in mediating various effects of the allergic reaction. Recent evidence has shown that they play a role in other diseases. Leukotrienes can be separated into the fairly well-characterized cysteinyl leukotrienes and the less well-characterized leukotriene B4. Effects of the leukotrienes are mediated through receptors that are expressed on a variety of cell types and can be modulated based on the inflammatory environment present. The pharmaceutical industry has long been interested in blocking leukotriene action. As such, two approaches have been developed that led to drugs approved for treating allergic disease. The most widely used class is the cysteinyl type 1 receptor antagonists, which block binding of the cysteinyl leukotrienes to the cell. The second class is an inhibitor of the 5-lipoxygenase enzyme that prevents synthesis of both the cysteinyl leukotrienes and leukotriene B4. This review focuses on the role that leukotrienes play in various diseases, with the emphasis on allergic diseases, and considers the rationale for choosing either a leukotriene antagonist or synthesis inhibitor as a treatment option.
Introduction In the late 1930s, the slow-reacting substance of anaphylaxis was described based on the identification of a mediator that, in an antihistamine-resistant fashion, mediated the slow in onset, but sustained, contraction of guinea-pig ileum smooth muscle. It was not until 1979 that this mediator was successfully identified as a group of compounds known as the cysteinyl leukotrienes (CysLTs). Leukotrienes (LTs) are derived from the metabolic breakdown of arachidonic acid and consist of not only the CysLTs, but also LTB 4 (Fig. 1). Biosynthesis of
LTs requires cellular activation by which membrane phospholipids are converted into arachidonic acid by the action of a family of enzymes termed phospholipase A 2 . Following activation, the enzyme 5-lipoxygenase (5-LO) translocates from the cytosol to the inner nuclear membrane where, in association with 5‑lipoxygenase– activating protein (FLAP), arachidonic acid is oxygenated to form 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) and then dehydrated to generate leukotriene A4 (LTA4) [1]. 5-LO is a calcium-dependent enzyme that is active in a variety of cells including mononuclear phagocytes, B lymphocytes, granulocytes, and mast cells. LTA4 is unstable, and it is converted to LTB 4 by LTA4 hydrolase; alternatively, LTA4 can be metabolized into the cysteinyl leukotriene LTC 4 by the enzyme LTC 4 synthase (LTC4S) (or the related enzyme microsomal glutathione transferase II, or MSGT-II) via conjugation of glutathione. LTC 4 is exported from the cell via the multi-drug transporter ATP-binding cassette (Abc) c1 where hydrolysis and the removal of the amino acid glutaminate occurs by action of serum γ-glutamyl transferase, giving rise to LTD4. LTE4 is produced following cleavage of a glycine residue from LTD4 by the enzyme dipeptidase, leaving behind the single amino acid cysteine from which this family derives its name [2]. Collectively, LTC 4, D4, and E4 constitute the CysLTs. LTs have been implicated in the pathogenesis of many diseases, and there has been an intense effort by the pharmaceutical industry to develop compounds that antagonize their action. This review examines the two approaches to limiting LT action—LT synthesis inhibitors and LT receptor antagonists—with the emphasis on their role in allergic disease.
Leukotriene Receptors Response to CysLTs is mediated through high-affinity interactions with two cloned receptors that are referred to as the CysLT1 and CysLT2 receptors. Although they share only 38% amino acid identity, both receptors are seven transmembrane domain G-protein–coupled receptors that in part utilize calcium as a second messenger [3,4]. The two receptors can be distinguished by their relative potency for binding CysLTs: CysLT1 receptor LTD4>LTC 4>>LTE4 and CysLT2 receptor LTD4 =LTC 4>>LTE4. Thus, the CysLT1
Leukotriene Synthesis Inhibitors Versus Antagonists Steinke and Culp 127
receptor has an approximately 50-fold higher affinity for LTD4 than that for LTC 4. The distribution of the CysLT receptors on peripheral blood leukocytes is shown in Table 1 [4–6]. It should be mentioned that there is some pharmacological evidence for a third CysLT receptor, because human pulmonary artery stimulated with LTC4 is resistant to inhibition with all known receptor antagonists [7]. Recently, the GPR17 orphan receptor has been shown to respond to uracil nucleotides and CysLTs and expression is found in the heart, brain, and kidney undergoing ischemic damage [8]. Whether this is the same receptor remains to be determined. High levels of expression of both the CysLT1 and CysLT2 receptors have been observed on eosinophils and mast cells, whereas only low levels of the CysLT1 receptor are expressed on neutrophils. Few circulating T lymphocytes express either class of receptor (approximately 4% to 8%); however, higher levels are seen in inflamed tissue [4,9]. In addition to these immune cells, the CysLT1 and 2 receptor has been found on smooth muscle cells and CysLT2 receptor is expressed on heart Purkinjie fiber cells, adrenal chromaffin cells, brain, and human umbilical vein endothelial cells (HUVEC) [5,10]. In contrast to lung fibroblasts, which express the CysLT1 receptor [11], nasal polyp–derived fibroblasts do not express either the CysLT1 or 2 receptors [12]. As with the CysLT receptors, two G-protein–coupled receptors, BLT1 and BLT2, have been identified as mediating action by LTB 4. The two receptors share 45% amino acid identity and it is believed they arose from gene duplication, because BLT2 uses the BLT1 promoter and its sequence overlaps a 5' untranslated region of a BLT1 splice variant. The BLT1 receptor displays higher affinity and specificity for LTB 4 than the BLT2 receptor [13]. The expression pattern for the receptors in peripheral blood leukocytes is shown in Table 1. In general, BLT1 receptor expression is highest in peripheral blood leukocytes with lower levels found on spleen, heart, brain, and lung fibroblasts [11,13]. Of the leukocytes, neutrophils and monocytes have the highest BLT1 levels, whereas expression in dendritic cells is absent. BLT2 receptors are more ubiquitously expressed with high levels observed in spleen, liver, ovaries, and peripheral blood leukocytes. Within the leukocyte population, it is interesting to note that high levels are found on both CD4+ and CD8+ T cell populations, B cells, and dendritic cells [14]. CysLT receptor expression can be modulated depending on cell type and stimulus. Stimulation with interleukin (IL)-4 increases cell surface expression of both the type 1 and 2 CysLT receptors on mast cells without altering mRNA or protein levels [15]. In contrast, IL-4 stimulated CysLT2 receptor mRNA production in HUVECs, and both IL-4 and IL-13 stimulated mRNA and cell surface expression of the CysLT1 receptor in human monocytes [16]. Similar to IL-4, interferon (IFN)-γ decreased CysLT1 receptor mRNA expression on human monocytes, while IFN-γ stimulated CysLT1 and CysLT2
Membrane phospholipid Phospholipase A2
Stimulus
Arachidonic acid 5-Lipoxygenase/5-LO activating protein (FLAP) LTA4 LTC4 synthase
LTA4 hydrolase
LTC4
LTB4 H-Glutamyl transferase
LTD4 Dipeptidase LTE4
Figure 1. Leukotriene synthesis pathway indicating the enzymes that are involved in each step of synthesis. LT—leukotriene. Current Allergy Reports AL07-2-1-08 fig. 1 240 pts. W/ 235 pts. D (20 x 19p6) Author: Steinke Editor:and Virginia Artist: receptor TE receptor mRNA production CysLT1 cell
surface expression on human airway smooth muscle cells [16]. IL-5 increased CysLT1 receptor mRNA and cell surface expression on a human eosinophil cell line [17]. Few studies exist on the modulation of the LTB 4 receptors. Of the cytokines, IFN-γ and IL-1β have been shown to increase mRNA and protein expression of the BLT1 receptor, tumor necrosis factor (TNF)-α, and IL-1β, leading to increases in the BLT2 receptor [18]. Non-cytokine stimulation of BLT1 receptor expression can be produced by lipopolysaccharide, dexamethasone, and LTB 4. Together, these studies broadly demonstrate the ability of cytokines to increase expression of both classes of LT receptors and provide a mechanism for increased expression and responsiveness of the receptors in inflamed tissue.
The Role of Leukotrienes in Allergic Diseases Chronic overproduction of CysLTs contributes to the bronchial hyperresponsiveness and chronic inflammation observed in asthma. CysLTs are potent and long-acting bronchoconstrictors in humans, approximately 1000 times greater than histamine. In vitro studies confirmed that CysLTs, with a minor contribution from histamine, mediate immunoglobulin (Ig) E-dependent contractions of human bronchi isolated from asthmatic lungs in response to allergen exposure [19]. Several clinical trials demonstrated that approximately 80% of the early bronchoconstriction caused by inhaled allergen in asthmatic patients can be eliminated with CysLT receptor antagonists and LT synthesis inhibitors [20]. Following inhaled allergen challenges in asthmatic patients, CysLTs are
128 Rhinitis
Table 1. Leukotriene receptor expression on leukocytes Cell type
CysLT1 receptor
CysLT2 receptor
BLT1 receptor
BLT2 receptor
Eosinophil
++
+
+
+
Monocyte
++
+
++
+
Alveolar macrophage
+
+
+
Unknown
Neutrophil
+
−
++
+
Mast cell
+
+
+
+
Basophil
+
+
+
−
CD4+ T cell
+
+
+
++
CD8+ T cell
Unknown
Unknown
+
++
B cell
+
+
+
++
Dendritic cell
+
++
−
+
BLT—leukotriene B receptor; CysLT—cysteinyl leukotriene; double plus—highly expressed; minus—not expressed; plus—expressed.
detected in the bronchoalveolar lavage (BAL) fluid and urinary LTE4 levels are markedly elevated. Using immunohistochemical staining of nasal mucosa obtained via turbinectomy in patients with allergic rhinitis (AR), CysLT1 receptors were localized to eosinophils, mast cells, macrophages, neutrophils, and vascular endothelial cells [21]. The authors also found expression of CysLT2 receptor mRNA in the tissue, but the cells responsible for this expression were not characterized. Nasal scrapings from patients with AR revealed that 5-LO, FLAP, LTC4S, and both of the CysLT receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells. Additionally, 5-LO, FLAP, and the CysLT1 receptor were expressed in a subset of neutrophils found in the nasal mucosa [6]. These studies show that allergic and inflammatory cells from the upper airway of patients with active seasonal allergic rhinitis produce LTs and express the CysLT receptors, thereby demonstrating the potential of CysLT receptor antagonists and LT synthesis inhibitors to treat upper airway symptoms in this patient population. In patients with chronic hyperplastic eosinophilic sinusitis (CHES) and nasal polyposis (NP), the role of LTs and CysLT receptors has not been extensively studied. A recent study compared CysLT1 receptor expression in CHES patients without or with aspirin intolerance [9]. Aspirin intolerance is associated with the dramatic overexpression of the enzyme LTC4S, primarily within eosinophils. Of the T cells found in these nasal biopsies, 32% expressed the CysLT1 receptor [9], in contrast to 4% to 8% of the T cells in peripheral blood [4]. This suggests that T cells expressing the CysLT1 receptors preferentially home to the nasal mucosa when CysLTs are produced, survive longer in the nasal mucosa, or have local induction of the receptor in the T H 2 cytokine milieu of the nasal mucosa. Following aspirin desensitization, patients have a decrease in the number of CD45+ leukocytes expressing the CysLT1 receptor [9] and a decrease in the sensitivity
to inhaled CysLTs [22]. Because CHES is characterized by CysLT overproduction, enhanced CysLT responsiveness [22], and CysLT receptor overexpression [9], it appears that CysLTs contribute to the hyperplastic inflammation and fibrosis of CHES/NP. The role of CysLTs in atopic disease, such as allergic rhinitis and asthma, has led to speculation that CysLTs may have an important role in atopic dermatitis (AD). Studies have shown higher urinary LTE4 levels in AD patients compared to normal controls, suggesting increased synthesis of CysLTs [23] and elevated LTB 4 levels in AD lesions [24]. However, the exact role of LTs in AD has yet to be determined. Chronic urticaria (CU), whether idiopathic or from a known reaction to cold, pressure, food additives, or nonsteroidal anti-inflammatory drugs (NSAIDs), is caused by a variety of mechanisms, all of which result in degranulation of cutaneous mast cells. Histamine is considered to be the major mediator of CU; however, CysLTs have been suggested to play a key role in late phase reactions of CU. Histamine 1 (H1)-receptor antagonists remain the standard treatment for CU, but many patients do not respond to antihistamines. A recent study demonstrated that after specific oral challenge in patients with CU and hypersensitivity to aspirin or food additives, both caused a significant increase in urinary LTE4 levels, compared to healthy subjects and patients with CU who tolerate both acetylsalicylic acid and food additives [25].
The Role of Leukotrienes in Nonallergic Diseases LTs play a wide variety of roles in diseases outside the allergic realm. In the cardiovascular system, LTs are formed via the 5-LO cascade and have potent proinflammatory activities. The 5-LO cascade is abundantly expressed by mononuclear cells, dendritic cells, mast cells, and neutrophilic granulocytes in the arterial walls
Leukotriene Synthesis Inhibitors Versus Antagonists Steinke and Culp 129 Figure 2. Locations of action for the leukotriene synthesis inhibitor and receptor antagonists. CysLT—cysteinyl leukotriene; LT—leukotriene.
Membrane phospholipid Phospholipase A2 Arachidonic acid 5-LO inhibitor Zileuton
5-Lipoxygenase/5-LO activating protein (FLAP) LTA4 LTA4 hydrolase
LTC4 synthase CysLT1 receptor antagonist Montelukast Pranlukast Zafirlukast
LTB4
LTC4, D4, E4
CysLT1
CysLT2
BLT1
BLT2
Dual BLT receptor antagonist LY-293111
of patients with atherosclerosis of the Current Allergy Reports AL07-2-1-08 fig. 2aorta, 324 coronary pts. W/ 180 pts.recruitment D (27 x 15) and activation of neutrophils, monocytes, Steinke Editor: TE arteries, and carotidAuthor: arteries [26]. In thisVirginia study, Artist: the cells and eosinophils, and stimulates the production of proexpressing 5-LO were markedly increased in advanced inflammatory cytokines and mediators that augment and atherosclerotic lesions, thus supporting a model of ath- prolong tissue inflammation. erogenesis where the 5-LO pathway evolves within the blood vessel wall during critical stages of lesion development. Cipollone et al. [27•] demonstrated that 5-LO is Pharmacological Inhibition of elevated in symptomatic compared with asymptomatic Leukotriene Action plaques and is associated with acute ischemic syndromes. To antagonize or to inhibit LTs, that is the question. In addition, a human genetic study has identified a sub- There has been an intense effort put forth by the pharpopulation with variant 5-lipoxygenase genotypes that maceutical industry to develop molecules that block LT has an increased relative risk for atherosclerosis, stroke, action. To date, only four have been approved for use and myocardial infarction [28]. in treating asthma or allergic rhinitis. The location of LTs in chronic obstructive pulmonary disease action of these molecules in the LT pathway is indicated (COPD) and asthma have different roles. Patients with in Figure 2. Zileuton is the only 5-LO inhibitor on the asthma have increased LTE 4 in exhaled breath conden- market and as such has the capacity to prevent synthesis sate (EBC), whereas patients with COPD do not. LTB 4 in of both the CysLTs and LTB 4. These attributes would EBC is increased in both asthmatic and COPD patients, seemingly make this the drug of choice; however, zileuthough this increase was more pronounced in the COPD ton suffers from a lack of potency, a half-life of 2 hours, group [29]. Moreover, LTB 4 concentrations were 2.5- and short duration of action requiring dosing four times fold higher in COPD subjects compared to age-matched a day. Furthermore, zileuton’s potential hepatic toxicity control subjects, suggesting a primary pathophysiologi- in some individuals necessitates periodic liver enzyme cal role for LTB 4 in COPD. testing. Montelukast, zafirlukast, and pranlukast all Acute inflammatory skin reactions are characterized act by antagonizing the CysLT1 receptor. The benefits by infiltration of leukocytes that cause increased blood of these drugs are that they can be taken once daily flow and vascular permeability. Invading leukocytes pro- and are generally well tolerated with few side effects duce LTB 4, a highly potent chemotactic agent. Intradermal reported. The downside is that only the CysLT1 receptor injections of LTB 4 induce dermal neutrophil infiltration in is blocked and they have no effect on effects mediated humans [30]. 5-LO gene expression is an intrinsic prop- by the CysLT2 receptor or on LTB 4 action. A few LTB 4 erty of human keratinocytes; however, only receptors for receptor antagonists have been developed, but none have LTC 4 have been found on human keratinocytes in culture. reached market at this time. One compound (LY293111) LTB 4 is increased in psoriatic lesions, but its synthesis by is currently in phase II clinical trials for pancreatic canepidermal cells remains unclear. When LTB 4 is applied cer. A LTA4 hydrolase inhibitor (DG051) is in phase I topically to human skin, intraepidermal micro-abscesses trials for the prevention of heart attacks. Neither comcontaining numerous intact neutrophils are formed, pound will be discussed further here. changes that are similar to those found in psoriatic skin Although montelukast, pranlukast, zafirlukast, and [30]. Interestingly, as in atopic dermatitis, LTB 4 levels were zileuton have all been approved for use in the treatment increased 6.6 fold in psoriatic lesions [31]. Unfortunately, of asthma, there are surprisingly few studies that have 5-LO inhibitors have so far been shown to be ineffective compared the efficacy of these drugs in a head-to-head in treatment of psoriasis. In acne vulgaris, LTB 4 induces manner. In a study on exercise-induced asthma, both
130 Rhinitis
montelukast and zileuton had a comparable level of prophylaxis as measured by protection from a drop in FEV1 following 4 minutes of exercise at early time points, but the protective effect of zileuton was lost in the singledose experiment at later time points due to shorter half-life [32]. CysLT receptor antagonists and LT synthesis inhibitors have been shown to produce a persistent and considerable improvement in baseline lung function in steady-state asthma [33]. In a recent study of children ages 2 to 5 years, montelukast decreased the number of viral-induced asthma exacerbations [34•]. Studies with zileuton were the first to demonstrate an improvement in the upper airways by relieving allergen-induced nasal obstruction [35]. Subsequent studies with LT receptor antagonists documented reduced eye symptoms, reductions in subjective symptoms, and decreases in objective measures following seasonal allergen exposure [36]. Both montelukast and pranlukast have since been approved for the treatment of rhinitis. As discussed above, CysLTs have important pro-inflammatory capabilities including the ability to promote eosinophilic inflammation in the airways and nasal mucosa. Other activities include increasing airway smooth muscle hyperreactivity, increasing vascular permeability, stimulating mucus secretion, and decreasing mucociliary clearance. The synergistic effects of CysLTs on the differentiation of eosinophil progenitor cells are partially blocked by addition of the CysLT1 receptor antagonist montelukast [37]. It is therefore not surprising that clinical trials of LT modifiers in both asthma and allergic rhinitis have shown reductions in circulating absolute eosinophil counts [38]. However, survival of eosinophils induced by CysLTs occurs in part through activation mediated through both the CysLT1 and CysLT2 receptors, indicating that a LT synthesis inhibitor might be more effective in blocking this effect. Although not approved, one can consider using LT modifiers in other allergic diseases. We have demonstrated increased levels of CysLTs in polyp tissue from patients with CHES as compared to tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue [39]. This study also found patients with CHES had increased mRNA transcripts for the proteins involved in the metabolic pathway of LT synthesis. LT modifiers are likely to provide benefit in CHES through direct reduction of eosinophil recruitment and activation in the sinuses, and through their ability to diminish eosinophilopoiesis and promote apoptosis. CysLT1 receptor antagonists (zafirlukast and montelukast) have been suggested to have efficacy in CHES/NP in uncontrolled trials [40]. Recently, this group has reported results of a double-blind placebocontrolled trial with montelukast. Postoperative CT scans of patients receiving montelukast showed either improvement or no change in comparison to the perioperative scans, whereas 30% of patients in the placebo group had CT scans that worsened following surgery. Endoscopic evaluation revealed that nasal polyps recurred in 60% of
the patients receiving placebo compared to only 25% in the montelukast group [41]. These findings are supported by two groups who were able to demonstrate that the recurrence rate of nasal polyps in aspirin-sensitive asthmatics was reduced when they were given montelukast [42,43]. In a placebo-controlled trial, the 5-lipoxygenase inhibitor zileuton was shown to reduce polyp size and restore sense of smell in subjects with aspirin-intolerant asthma and sinusitis [44]. Inhibition of 5-LO has broader implications, because in addition to CysLTs, zileuton will block production of other pro-inflammatory lipids, including LTB 4 and 5-hydroxyeicosatetraenoic acid (5(S)HETE). In contrast to the CysLT1 antagonists, it is interesting to speculate that zileuton’s ability to block CysLT production, and subsequently to inhibit activation mediated through both CysLT1 and CysLT2 receptors, contributes to its clinical efficacy in these subjects. Inflammation in skin diseases such as AD and CU appears to be mediated in part by LTs. Case reports have observed skin improvements in AD patients with use of CysLT receptor antagonists and LT synthesis inhibitors [45]. A pilot study of six patients examining the ability of zileuton to improve atopic dermatitis showed promising results. Patients were given 600 mg zileuton four times daily for 6 weeks without the use of their usual AD medication. Significant improvements were observed in objective skin erythema scores and disease dissatisfaction scores with a trend towards improvement of pruritus scores [46]. A chart review examining the use of LT modifiers in treatment of chronic urticaria revealed that 10 of 18 patients who were given LT modifiers (montelukast, zafirlukast, or zileuton) along with an antihistamine had resolution of their symptoms within 1 month [47]. These observations were supported by a recent study which suggested that a CysLT receptor antagonist was effective in the treatment of refractory idiopathic CU [48]; however, a subsequent study did not support these findings [49]. Controlled trials with LT modifiers are needed for both diseases. The proliferative effects mediated by CysLTs on myofibroblasts and smooth muscle are blocked by the less selective receptor antagonists pranlukast and pobilukast, but not by the highly CysLT1-receptor–specific compound zafirlukast, suggesting that this is not mediated by the CysLT1 receptor [50]. CysLT receptors are present on endothelium where they promote vascular leakage and stimulate expression of P‑selectin [51]. However, CysLT1 receptor antagonists fail to block CysLT-induced expression of P-selectin, again supporting a role for a different class of receptors in this aspect of CysLT-mediated inflammation [51]. This inability of selective CysLT1 receptor antagonists to inhibit pro-inflammatory effects of CysLT on endothelium may reflect the selective expression of CysLT2 receptors on these cells. Unique functions of CysLT receptors have also been described on mast cells [15]. When primed with IL-4, engagement of CysLT1
Leukotriene Synthesis Inhibitors Versus Antagonists Steinke and Culp 131
receptors was associated with generation of IL-5, TNFα, and CCL4 (MIP-1β), whereas engagement of CysLT2 receptors was uniquely associated with production of CXCL8 (IL-8) and IL-16. CysLT2 receptors are prominently expressed in cardiac myocytes. Support for a role for CysLT2 in fibrosis is derived from observations that conditions associated with intravascular activation of eosinophils, such as hypereosinophil and Churg-Strauss syndromes, often lead to the development of endomyocardial fibrosis. Together, these observations support a direct causative role for CysLTs acting synergistically through both CysLT1 and CysLT2 receptors and suggest that a LT synthesis inhibitor would be more effective than a receptor antagonist in blocking these effects. Beyond asthma and allergic diseases, are there indications where modification of the LT response is warranted? The answer is yes. Studies have shown that the arachidonic acid pathway is involved in the inflammation that develops in acne. A pilot study was performed on patients with moderate inflammatory acne who were given zileuton, 600 mg four times a day. At 12 weeks, there was a significant decrease in inflammatory lesions (70%) and trends toward decreases in noninflammatory lesions and sebum lipid levels [52]. Larger double-blind studies are warranted to confirm these results. Despite the strong physiological and genetic links of LT production and cardiovascular disease, few studies have examined the role of LT modification in prevention of or recovery from cardiovascular disease. A phase IIa study was conducted with the FLAP inhibitor DG-031 in a group of patients with a history of myocardial infarction who carried at-risk alleles for the FLAP or LTA4 hydrolase gene. At a dose of 750 mg/day of DG-031, the ex vivo production of LTB 4 decreased 26% and that of myeloperoxidase decreased 12% [53]. COPD is characterized by a neutrophilic infiltrate and expression of LTB 4. Based on the production of LTB 4, it seems reasonable to predict that a LT synthesis inhibitor would be efficacious. Interestingly, a recent study showed that a CysLT receptor antagonist in routine treatment protocols can produce additive improvements in pulmonary function tests, dyspnea scores, and quality of life in patients with stable, moderate-to-severe COPD [54]. Other diseases where modulation of LTs might be important are obesity, multiple sclerosis, ischemia, cancer, and sickle cell disease; however, once again, more studies are needed to determine the value of this treatment in these diseases.
pathogenesis of allergic and nonallergic diseases led to the development of drugs that either blocked LT action on cells or inhibited LT synthesis. The choice as to which type of drug to use depends on the disease and its problematic symptoms. For mild asthma and allergic rhinitis, a LT antagonist is often sufficient for relief of symptoms. For severe asthma, aspirin sensitivity, sinus disease, and LTB 4 -mediated diseases, the choice of a LT synthesis inhibitor may provide more relief than a receptor antagonist.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. 3. 4. 5.
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Conclusions LTs mediate a myriad of pro-inflammatory activities through their high-affinity interaction with G-protein– coupled receptors. These receptors demonstrate broad but unique patterns of expression on immune and nonimmune cells. The important role that LTs play in the
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