Role of prostaglandins in asthma

Immunol Allergy Clin N Am 22 (2002) 827 – 844

Role of prostaglandins in asthma R. Stokes Peebles Jr, MD a, J.R. Sheller, MD a,b,* a

Division of Allergy, Pulmonary, and Critical Care Medicine, Center for Lung Research, Vanderbilt University School of Medicine, T-1217 MCN, Nashville, TN 37215, USA b Respiratory Care, Vanderbilt University Hospital, 22nd and Garland, Nashville, TN 37215, USA

Prostaglandins are autacoid mediators that have important regulatory roles in human inf lammatory diseases. This article focuses on the immunologic and physiologic roles of prostanoids in asthma, an inf lammatory condition that affects 5% to 10% of the population [1]. The strongest predisposing factor for the development of asthma is allergy; therefore, the immunologic effects of prostanoids on allergic inf lammation are of great importance [2]. Prostanoids affect smooth muscle tone, vascular permeability, and mucus production, which are important features of asthma [2]. Selected data from in vitro and in vivo studies of animals and humans are summarized to illustrate the presumed role of prostanoids in asthma. Prostanoids are generated in a multistep process that begins with the formation of arachidonic acid by the cleavage of membrane phospholipids by phospholipase A2 (PLA2) [3]. Arachidonic acid then can be metabolized by the cyclooxygenase (COX) enzymes to form the unstable intermediary prostaglandin G2 (PGG2), which is converted to PGH2 [3]. Arachidonic acid also may be metabolized by other enzymes such as 5-lipoxygenase (5-LO), which results in the formation of the leukotrienes. PGH2 can be converted by cell-specif ic enzymes and isomerases into the five primary prostanoids: PGD2, PGE2, PGF2a, , PGI2, and thromboxane (Fig. 1) [3]. Each prostanoid signals through distinct members of a family of G-protein – coupled prostanoid receptors (Table 1) [4]. PGF2a, PGI2, and thromboxane signal through unique receptors (FP, IP, TP, respectively). PGD2 signals through two known receptors, DP and CRTH2 [5,6]. PGE2 signals through four receptors: EP1, EP2, EP3, and EP4 [4]. The isoprostanes are prostaglandin-like compounds that are formed nonenzymatically by the free radical-catalyzed oxygenation of bound arachidonate This article was supported by K08-HL-03730, GM 15431, R01-AI-45512, the American Lung Association of Tennessee, and the American Academy of Allergy, Asthma and Immunology ERTAward. * Corresponding author. Division of Allergy, Pulmonary, and Critical Care Medicine, Center for Lung Research, Vanderbilt University School of Medicine, T-1217 MCN, Nashville, TN 37215, USA. E-mail address: [email protected] (J.R. Sheller). 0889-8561/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 8 9 - 8 5 6 1 ( 0 2 ) 0 0 0 2 4 - 3

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Fig. 1. The pathway of arachidonic acid metabolism leading to the formation of the prostanoids and leukotrienes.

[7]. This novel group of compounds is biologically active and formed in substantial amounts in humans and experimental animals [8]. Most compounds have not been investigated to any extent, and the lack of a means to specif ically inhibit their production and the number of different regioisomers has made characterization of their role in asthma diff icult. Several of the prostanoids are known to have an important role in allergic inf lammation, and allergen-induced inf lammation is an important component of asthma. Immune recognition of common environmental antigens is initiated by specialized antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B lymphocytes [9]. These APCs incorporate antigen through a variety of mechanisms, depending on the specific APC, and process the antigen so that antigenic fragments can be presented to CD4 + T lymphocytes by way of major histocompatibility complex class II molecules on the APC surface. CD4 + T lymphocytes generally are divided into two main classes (Type 1, Type 2) that are characterized by the cytokine array that is produced by the cell. The Type 2 lymphocyte is critical for the development of allergic responses and anaphylaxis. Type 2 cells, mast cells, and basophils produce interleukin 4 (IL-4), an important factor for B lymphocytes in switching antibody production to the immunoglobulin E (IgE) isotype. Type 2 cells additionally make a variety of other pro-allergy Table 1 Prostanoid receptors Prostanoid

Receptor

PGI2 PGF2a Thromboxane PGD2 PGE2

IP FP TP DP, CRTH2 EP1, EP2, EP3, EP4

Abbreviations: PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2a, prostaglandin F2a; PGI2, prostaglandin I2.

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inf lammatory cytokines, such as IL-5, IL-9, and IL-13. IL-5 is an important eosinophil regulatory factor. IL-9 has been described as a factor that regulates IgE production, mast cell growth, and mucus production, whereas IL-13 is believed to be a central mediator in airway hyperreactivity. Interferon g (IFN-g) is the signature cytokine produced by CD4 + T lymphocytes that are defined as Type 1 cells, and this cytokine is presumed to negatively regulate allergic responses by inhibiting development of CD4 + T lymphocytes cells to a Type 2 phenotype.

Cyclooxygenase enzymes There are two structurally distinct cyclooxygenase enzyme isoforms: COX-1 and COX-2. COX-1 is expressed constitutively in most mammalian tissues and is presumed to be involved in homeostatic prostanoid synthesis [10,11]. COX-2 expression is induced by inflammatory mediators, such as IL-1b and TNF-a, which are present in the bronchoalveolar lavage (BAL) f luid of asthmatic patients [12]. These cytokines can induce COX-2 expression in several culture systems of cells, including airway epithelial cells [13,14], airway smooth muscle cells [15,16], and airway fibroblasts [17]. The capacity of nonsteroidal anti-inf lammatory drugs (NSAIDs) to inhibit COX-2 activity may constitute their major therapeutic effect, whereas inhibition of COX-1 may result in their undesired side effects [18,19]. There have been conf licting reports about the expression of COX-2 in the asthmatic lung. A four-fold increase in the level of immunostaining of bronchial epithelial COX-2 has been reported in asthmatic subjects compared with that in nonasthmatic controls [20]. Another group found no significant differences in the level of immunostaining among patients with asthma, patients with chronic bronchitis, or controls without lung disease [21]. Reddington and colleagues found that expression of COX-2 mRNA and immunoreactive protein are increased in the airway epithelium of asthmatics who have not been treated with corticosteroids, compared with nonasthmatic controls. Asthmatics who received corticosteroid therapy had decreased expression of COX-2 [22]. There may be a complex relation between cytokines that are involved in the allergic response and COX-2 expression. In one study, IL-4 suppressed COX-2 expression and prostanoid synthesis in human monocytes and macrophages, and monocytes were more susceptible to this effect than were alveolar macrophages [23]. In asthmatic subjects, increased levels of TNF-a might lead to COX-2 induction, and increased levels of IL-4 might lead to COX-2 inhibition. Monocytes and alveolar macrophages had greater COX-2 expression when patients with atopic asthma were given a week of prednisone therapy, whereas the same corticosteroid treatment of normal subjects resulted in inhibition of COX-2 expression [24]. It was hypothesized that in addition to the well-characterized, direct corticosteroid inhibition of COX-2, corticosteroids could act indirectly by reducing IL-4 (and perhaps IL-13), thereby allowing TNF-a induction of COX-2. In vitro, corticosteroids also reduce COX-2 immunoreactivity in airway epithelial cells, but have little effect on COX-1 immunoreactivity [25]. Cortico-

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steroids reduce basal and bradykinin-induced levels of PGE2 in airway epithelial cells, suggesting that COX-2 is the major producer of PGE2 in airway epithelium [25]. COX-1 and COX-2 mRNA also can be detected in resting human T lymphocytes [26]. COX-1 expression in T lymphocytes does not seem to be altered by T-cell activation, whereas T-cell activation increases levels of COX-2 mRNA, resulting in increased levels of COX-2 protein and COX activity [26]. Both COX isozymes have roles in T-lymphocyte development [27]. COX expression is present in the resident airway cells and in cells of the adaptive immune response. Levels of cyclooxygenase products are increased in the BAL f luid of allergic asthmatics, compared with levels in nonasthmatic individuals, and are increased further after allergic antigen challenge in the airways. Liu and co-workers found that BAL f luid levels of PGD2 and PGF2a were 12- to 22-fold greater in asthmatics than in nonallergic subjects and were 10 times greater in allergic asthmatics than in subjects with allergic rhinitis who were not asthmatic [28]. In another study of the presence of prostanoids in the BAL f luid of allergic asthmatics, Liu found that 5 minutes after segmental allergen challenge, the levels of PGD2, thromboxane B2, and 6-keto-PGF1a, a PGI2 metabolite, increased 17- to 208-fold [29]. Prednisone treatment for 3 days before segmental allergen challenge had no effect on the levels of these prostanoids in BAL f luid [30]. To investigate the role of the COX enzymes in allergic bronchospasm, researchers gave indomethacin, a nonselective COX inhibitor that blocks COX-1 and COX-2, to subjects before allergen challenge. Indomethacin had no effect on baseline pulmonary function in allergic asthmatics or nonasthmatic subjects with allergic rhinitis [31]. After indomethacin treatment, however, nonasthmatic subjects with allergic rhinitis had greater sensitivity to allergen challenge as measured by the change in the forced expiratory volume in 1 second (FEV1) and specific airway conductance [31]. Indomethacin treatment that was given before allergen challenge caused a small but significant decrease in specific airway conductance in the allergic asthmatic subjects; indomethacin had no effect on allergen-induced changes in FEV1 [31]. Other investigators found that indomethacin treatment had no significant effect on baseline airway responsiveness to histamine and no effect on the immediate- or late-phase pulmonary response to allergens in allergic asthmatics [32,33]. In regard to exercise-induced asthma, indomethacin pretreatment does not alter bronchoconstriction after exercise, but indomethacin pretreatment does prevent refractoriness after exercise in asthmatic subjects [34]. The authors’ findings with indomethacin in a murine model of allergic inf lammation are more dramatic. Compared with vehicle-treated mice, mice given indomethacin in the drinking water during the induction of allergic airway disease had increased Type 2 cytokines in the lungs, increased pulmonary eosinophilia, and greater airway responsiveness to methacholine [35]. In similar studies of the development of allergic lung disease in mice that were deficient in the COX-1 and COX-2 synthase genes, COX-1 – deficient mice had increased pulmonary eosinophilia, increased serum IgE levels, and greater airway responsiveness compared with COX-2 – deficient and control mice that expressed COX-1 and COX-2 [36]. Compared with control mice, COX-2– deficient mice

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had increased serum IgE levels compared but no difference in pulmonary eosinophilia or airway responsiveness [36]. Because COX-1 critically affects the transition from CD4
CD8
cells to CD4 + CD8 + cells, and because COX-2 has an important role in early thymocyte proliferation and differentiation and subsequent maturation of the CD4 + T-lymphocyte lineage [27], the authors used pharmacologic inhibitors of COX-1 and COX-2 to avoid any confounding factors of developmental T-lymphocyte abnormalities in COX-1 – and COX-2– deficient mice. Mice that were treated with the COX-1 inhibitor (SC58560), COX-2 inhibitor (SC58236), or indomethacin during the development of allergic airway disease had augmented lung levels of IL-13, increased lung eosinophilia, and increased airway responsiveness compared with vehicle-treated mice [113]. Because the inhibition of COX during the development of allergic airway disease resulted in increased allergic inf lammation and airway responsiveness, these results suggest that a COX product may restrain allergic inf lammation and might be a therapeutic target for the treatment of asthma. In these murine studies, COX inhibition was present throughout the entire development of allergic disease, from the initial stage of antigen presentation and throughout all airway allergen challenges. In the human studies that used indomethacin, COX inhibition occurred only at the time of an airway challenge, long after the regulatory elements of allergic inf lammation in the lung had been set in place. The animal models of COX inhibition, which used either the COX-1 – and COX-2– deficient mice or used the specific or nonspecific COX inhibitors, do not represent models of aspirin-induced asthma, because the COX inhibitors have no direct inf luence on airway responsiveness, but rather modulate the allergic responses. Ex vivo studies often suggest that COX inhibition promotes Type 1 cytokine responses [37]. Pretreatment of spleen cells with indomethacin induces IFN-g production, but not IL-4 production, in cells from BALB/c, C3H/HeN, and C57/ B6 mice; in this ex vivo system, indomethacin treatment has the same effect as IL-12 administration [37]. This dichotomy between in vivo and ex vivo effects of COX inhibitors serves as a caution against the extrapolation of findings in isolated cell systems to the intact animal.

Prostaglandin D2 PGD2 is the most abundant COX product that results from IgE-mediated degranulation of mast cells [38,39]. CD4 + Type 2 cells, but not Type 1 cells, express PGD synthase [40]. Stimulation of Type 2 cells with coordinated expression of COX-2 induces the production of PGD2 by Type 2 cells [40]. In human models of allergen challenge, levels of PGD2 are increased in the BAL f luid of asthmatic subjects [41], but not in the sputum of allergen-challenged allergic asthmatics [42]. PGD2 levels are elevated in nasal lavage f luid in patients with allergic rhinitis [43], in tears in patients with allergic conjunctivitis [44], and in f luids from experimentally produced skin blisters in patients with late-phase skin reactions [45]. PGD2 is a potent bronchoconstrictor and vasodilator [46].

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Administration of PGD2 to the nares produces a 10-fold increase in nasal resistance compared with histamine and produces a 100-fold greater effect than does bradykinin [47]. PGD2 also can induce vascular leakage in the conjunctiva and skin [48] and can lead to the recruitment of eosinophils in the conjunctiva [49] and trachea [50], suggesting that it may have a pathogenic role in allergic disease. The identified human cellular receptors for PGD2 include DP and CRTH2. DP is a heterotrimeric, GTP-binding, protein-coupled, rhodopsin-type receptor that is specific for PGD2 [51]. The role of PGD2 in the development of allergic disease has become clearer with the creation of a mouse that lacks DP, resulting in the prevention of DP signaling in this animal [6]. Allergically sensitized and challenged mice that lack DP have significantly decreased BAL concentrations of IL-4, IL-5, and IL-13, compared with control mice, and have no change in the levels of IFN-g in the BAL [6]. Compared with control mice, DP-deficient mice have decreased BAL cellular inf lux, with fewer eosinophils and lymphocytes, but there is no difference in the levels of macrophages in the BAL between the two groups [6]. In a protocol with a low dose of allergen challenge, allergen-induced airway responsiveness was also significantly decreased in the DP-deficient mouse compared with that in wild-type controls [6]. Serum IgE levels were not different between the DP-deficient mice and control mice [6], suggesting that the production of IgE may be upstream of PGD2 in controlling the events that modulate allergic inf lammation or that IgE may not be an important regulator in determining the degree of Type 2 inf lammation and airway responsiveness in the murine model. The DP-receptor antagonist S-5751 has been used in various allergen challenge models in the guinea pig [52]. Administration of this antagonist decreased allergeninduced, immediate-phase sneezing; nasal obstruction; vascular leakage into the mucosa; late-phase eosinophil inf lux; and mucosal plasma exudation. In the lung, the antagonist significantly reduced allergen-induced BAL eosinophilia [52]. CRTH2 is a seven-transmembrane receptor for PGD2 that is expressed preferentially on CD4 + Type 2 lymphocytes, eosinophils, and basophils in humans [5]. PGD2 signaling through CRTH2 results in intracellular calcium mobilization and chemotaxis of Type 2 cells [5]. Unlike DP, signaling through CRTH2 can cause PGD2-dependent chemotaxis of blood eosinophils and basophils, but not neutrophils [5,53]. This effect is the opposite of what would have been expected with PGD2 signaling through DP, which increases adenyl cyclase when binding with ligand [4]. Increasing adenosine 30,50-cyclic monophosphate (cAMP) in eosinophils, which occurs with DP signaling, abrogates eosinophil leukotriene C4 (LTC4) release, chemotaxis, and degranulation [54,55]. PGD2 signaling through CRTH2 can increase allergic inf lammation and perhaps augment asthmatic responses.

Prostaglandin E2 PGE2 is a major COX product of the airway epithelium and smooth muscle [56,57]. Pavord and Tattersfield have hypothesized that endogenous PGE2 may

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be bronchoprotective in human asthma, and abundant evidence supports this supposition [58]. PGE2 that is released from epithelial cells can inhibit vagal cholinergic contraction of airway smooth muscle [59]. There is a negative correlation between the sputum eosinophil count and sputum levels of PGE2 in asthmatics [60]. In human studies, PGE2 inhalation inhibits the immediate- and late-phase pulmonary responses to inhaled allergen [61,62]. Compared with inhalation of vehicle, inhalation of PGE2 decreases the change in methacholine airway reactivity and reduces the number of eosinophils after inhaled allergen challenge [61]. PGE2 blunts exercise- and aspirin-induced bronchoconstriction in patients who are sensitive to these challenges [63,64]. Although PGE2 has significant effects on pulmonary function in challenge models, it has no effect on baseline FEV1 or methacholine reactivity [62]. The results from these studies suggest that PGE2 has a greater immunomodulatory effect than a direct effect on airway caliber. This theory is supported by the fact that PGE2 inhalation before segmental allergen challenge significantly reduced the BAL levels of PGD2, an important product of mast cell degranulation, and the cysteinyl leukotrienes (Fig. 2) [65]. The rapid metabolism of PGE2 led investigators to use the more stable, orally active PGE1 analogue, misoprostol, in studies of allergen-induced airway inf lammation and lung function in animals and humans. Inhaled misoprostol or PGE2 blocked the acute bronchospasm that was caused by inhaled allergen in sensitized guinea pigs. Misoprostol reduced BAL eosinophilia by 72% 24 hours after allergen challenge [66]. Misoprostol also has been studied in aspirinsensitive asthmatics but was not found to have an impact on pulmonary function, b2-agonist use, or asthma severity score [67]. In mild asthmatics, misoprostol had no effect on baseline lung function or histamine reactivity and had significant gastrointestinal side effects in one third of the study subjects [68]. In vitro studies do not support the human in vivo studies that suggest PGE2 decreases allergic inf lammation. In vitro PGE2 inhibits lymphocyte production of the Type 1 cytokines IL-2 and IFN-g, promoting T-cell differentiation toward a Type 2 cytokine profile [69 – 72].The in vitro effects of PGE2 in promoting production of Type 2 cytokines may be regulated at the stage of antigen presentation. In one study, myeloid dendritic cells that matured in the presence of IFN-g induced responses from the Type 1 CD4 + T lymphocytes, whereas dendritic cells that matured in the presence of PGE2 induced responses in Type 2 T cells [73]. If PGE2 increases the production of Type 2 cytokines primarily through its activity at the time of antigen presentation, this finding would not necessary contradict the in vivo human studies that suggest that PGE2 is antiinflammatory. Acute antigen-challenge models probably more accurately reflect effector cell function, because allergic sensitization to an antigen occurs much earlier in life. In addition to the effects of PGE2 on the development of CD4 + Type 1 and Type 2 cells, PGE2 has important effects on other inf lammatory cells that are presumed to be pathogenic in asthma. In a cell-culture system, PGE2, cAMP, and an agonist for the PGE2 receptor (EP2) inhibited spontaneous eosinophil

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Fig. 2. Levels of prostanoids and leukotrienes for each subject during their control period at baseline and after allergen instillation (Placebo) and for each subject during their crossover period after administration of inhaled PGE2 before bronchoscopy at baseline and after allergen administration (PGE2). (A) Nebulized PGE2 significantly reduced PGD2 levels in BAL f luid after allergen challenge ( P = 0.014). (B) Nebulized PGE2 reduced the levels of cysteinyl leukotrienes in BAL f luid after allergen challenge by 64% ( P = 0.049). (From Am J Respir Crit Care Med 2000;162:637 – 40; with permission.)

apoptosis [74]. By augmenting eosinophil survival, PGE2 might increase the inf lammatory potential of these cells in asthma. In contrast, PGE2 also has been reported to decrease eosinophil chemotaxis, aggregation, degranulation, and IL-5-mediated survival [54,75]. How these findings can be reconciled and the relative importance in vivo of the ex vivo actions of PGE2 remain unclear. Prostaglandin E2 regulates the production of granulocyte-macrophage colonystimulating factor (GM-CSF) from human airway smooth muscle cells [76]. Cultured human airway smooth muscle cells that are treated with the COX inhibitor indomethacin have increased production of GM-CSF [76]. Exogenous PGE2 down-regulates this indomethacin-induced GM-CSF production, suggest-

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ing that PGE2 may act as a braking mechanism to decrease GM-CSF concentrations and the inf lammation that is associated with this cytokine [76]. In contrast, PGE2 enhances the IgE-mediated production of IL-6 and GM-CSF by mast cells by signaling through the EP1 and EP3 receptors [77]. PGE2 also has been reported to have varying effects on the mast cell production of differing mediators. Depending on the mast cell population and the timing of PGE2 treatment, PGE2 has been reported to inhibit [78 – 80] or augment [81,82] the release of histamine and other inf lammatory mediators. Some of the differing effects of PGE2 administration in in vivo and in vitro studies may be related to the fact that PGE2 signals through four distinct Gprotein – coupled receptors, which have distinct and sometimes opposite effects. All four receptor subtypes are present in the lung [83,84]. Signaling through the EP1 receptor increases levels of inositol triphosphate and diacylglycerol, resulting in increased levels of Ca2 + in cells and smooth muscle contraction. EP1 expression is greatest in the mouse kidney and is present at low levels in the mouse lung [85]. Activation of the EP2 and EP4 receptors increases the intracellular cAMP concentration and relaxes smooth muscle [86]. Stimulation of the EP2 receptor inhibits mediator release from mast cells and basophils. EP2 is expressed most abundantly in the uterus, lung, and spleen [83]. EP4 expression is greatest in the kidney and peripheral blood leukocytes, but there is high level of expression in the thymus, lung, and a number of other tissues [87]. EP3 receptors cause smooth muscle contraction by decreasing the rate of cAMP synthesis [88]. A unique feature of the EP3 receptor is the diversity that is created by multiple splice variants that produce alternate sequences in the C-terminal tail of this receptor subtype; however, the functional significance of these alternative splice variants is unknown [83]. In general, these splice variants inhibit cAMP generation; in contrast, signaling through EP2 and EP4 elevates cAMP levels [83]. The actions of PGE2 are myriad and potentially competing, depending on the relative contribution of the receptor that is activated.

Prostagladin F2A There are fewer reports of the role of PGF2A in asthma compared with reports of PGD2 or PGE2. Inhalation of PGF2A results in a dose-related decrease in specific airway conductance in healthy and asthmatic subjects [89 – 91]. A wide variability in the pulmonary function response to PGF2A has been reported in asthmatics, whereas there is a relatively small interindividual variation in nonasthmatic subjects [91]. After inhaling PGF2A, some patients develop wheezing, coughing, and chest irritation within 3 to 4 minutes after inhalation [91]. Watery sputum also may develop shortly after PGF2A inhalation [91]. The maximal decrease in specific airway conductance after inhaling PGF2A occurs after 6 minutes, and recovery occurs within 30 minutes [91]. Asthmatics have an approximate 150-fold greater sensitivity to PGF2A than do nonasthmatics, whereas asthmatics are only 8.5 times more sensitive to histamine than are

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nonasthmatic controls [91]. There is also much less variation in individual responses to histamine compared with responses to PGF2A, but sensitivity to both drugs seems to correlate [91]. In general, women seem to be less sensitive to the bronchoconstrictor effect of PGF2A than are men [91]. PGE2 and isoprenaline augment recovery from the decrease in pulmonary function caused by PGF2A inhalation; however, atropine, disodium cromoglycate, and flufenamic acid do not prevent PGF2A-induced bronchoconstriction [91]. PGF2A and PGE2 decrease concentrations of exhaled nitric oxide in normal and asthmatic subjects [92]. The mechanism and importance of this effect are unknown. Evidence suggests that PGF2A may have a role in airway inflammation in asthma. In asthmatic subjects, the sputum eosinophil count correlated with the log sputum PGF2A concentrations [60]. This finding contrasted the negative correlation found between sputum eosinophilia and PGE2 levels and the lack of correlation between the number of sputum eosinophils and concentrations of sputum cysteinyl leukotrienes, thromboxane, and PGD2 [60]. Tissue distribution of the expression of FPreceptor mRNA is highest in the ovarian corpus luteum, followed by the kidney, with lower-level expression in the lung, stomach, and heart [93].

Prostaglandin I2 PGI2, or prostacyclin, is a potent vasodilator and platelet inhibitor that has important vascular effects [94,95]. Evidence for its role in allergy is less developed. Urinary PGI2-derived products have been reported to be significantly increased in acute asthma exacerbations [96], and the stable metabolite of PGI2, 6-keto-PGF1A, is increased roughly 20-fold after segmental allergen challenge in atopic asthmatics [29]. Inhaled PGI2 at concentrations up to 500 Mg/mL did not affect specific airway conductance in mild asthmatics, but there was a doseresponse decrease in FEV1 and maximal expiratory flow at 30% vital capacity [97]. Despite the decrease in FEV1 with inhaled PGI2, PGI2 protected against bronchoconstriction induced by PGD2 and methacholine [97]. One explanation for this apparent paradox is that the potent vasodilator effect of PGI2 might cause airway narrowing through engorgement of the mucosa, which might decrease the spasmogenic effect of PGD2 and methacholine by favoring their clearance from the airway [97]. Other investigators have shown that, compared to placebo, premedication with inhaled PGI2 has no effect on pulmonary function during the immediate-phase reaction after allergen challenge [98]. Nebulized PGI2 protects against the bronchoconstriction that is caused by water delivered by ultrasonic mist and exercise-induced bronchoconstriction [99]. Oral administration of a stable PGI2 analogue, OP-41483, had no effect on baseline FEV1 nor methacholine reactivity in asthmatic subjects, but no verification of drug concentration in the airway was done [100]. Intravenous PGI2 does not change bronchial obstruction in aspirin-sensitive asthmatics, but PGI2 accentuated aspirin-induced rhinorrhea in these subjects, perhaps because PGI2 causes vasodilation of the blood vessels in the nasal mucosa [101].

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The authors have studied the effects of PGI2 in a murine model of allergic inflammation. Mice that overexpress the PGI2 synthase gene and that have significantly elevated levels of PGI2 metabolites in their urine do not have significant differences in the production of Type 2 cytokines, BAL eosinophilia, or airway responsiveness compared with their littermate controls. Other investigators have studied the development of allergic airway disease in mice that lack the PGI2 receptor, IP. There was no difference in airway responsiveness in IP-deficient mice that were sensitized and challenged with allergen compared with their littermate controls (S. Austin, G. FitzGerald, personal communication, 2002). These results support the contention that PGI2 has little effect in the pathophysiology of allergic asthma, but longer-term interventional studies with PGI2 analogues in human asthma are necessary.

Thromboxane A2 Thromboxane A2 is the predominant product of the arachidonic acid metabolism of platelets and is a potent platelet-aggregating agent [95]. After generation, thromboxane A2 is nonezymatically hydrolyzed to thromboxane B2, which is metabolized further to the principle urinary metabolites 2,3-dinorthromboxane B2 and 11-dehydro-thromboxane B2 [102]. It has a half-life of approximately 30 seconds [39], and because of this property, there is a dearth of data on the in vivo effects of thromboxane A2 in the human airway. Thromboxane B2 does not cause bronchoconstriction of human airway in vivo [96]; however, thromboxane A2 is a potent stimulant of smooth muscle contraction in vitro [95]. Evidence suggests that thromboxane A2 may be important in the regulation of acute asthma exacerbations. In one study, a 4- to 6-fold increase in the levels of thromboxane A2 metabolites was found in the urine of patients who were admitted to the hospital with asthma compared with the levels in nonsmoking controls who were admitted for reasons other than asthma [96]. Some investigators found that inhaled allergen challenge in allergic asthmatics resulted in an increase in urinary excretion of thromboxane A2 products [33,103], whereas others have not found such an increase [96]. Inhibition of platelet COX by lowdose aspirin prevented an increase in urinary 2,3-dimer thromboxane, suggesting that allergen inhalation causes platelet activation. When allergic asthmatics were pretreated with indomethacin before an inhaled allergen challenge, there was a significant decrease in urinary thromboxane A2 metabolites but no change in pulmonary function [33]. In a human model of ozone-induced hyperresponsiveness, significant increases in BAL concentrations of thromboxane A2 and airway neutrophilia were reported [104]. Similarly, inhalation of LTB4 also resulted in increased levels of thromboxane A2 and neutrophils in BAL fluid [105]. Thromboxane A2 antagonists have been used in challenge models to dissect out the influence of thromboxane on allergen-induced bronchoconstriction. The thromboxane A2-receptor antagonist, BAY u3405, has been reported to decrease bronchial reactivity to PGD2 in humans and as having no effect on airway

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responsiveness to bradykinin [106]. In guinea pigs, BAY u3405 inhibited bronchoconstriction that was caused by the inhaled thromboxane A2 agonist U46619, PGD2, PGF2A, LTC4, and LTD4 [107]. A thromboxane synthetase inhibitor, OKY-046, did not alter bronchoconstriction to PGD2 or PGF2a, but did inhibit the decrease in pulmonary function to LTC4 and LTD4 [107]. These results indicate that the bronchoconstrictive effects of PGD2, PGF2A, LTC4, and LTD4 in the guinea pig partly are mediated through the thromboxane A2 receptor.

Prostaglandins in aspirin-induced asthma Approximately 10% of asthmatics experience an asthma exacerbation after using aspirin or other NSAIDs [108]. Patients with aspirin-intolerant asthma (AIA) have marked overexpression of LTC4 synthase, an enzyme that converts LTA4 to the cysteinyl leukotrienes LTC4, LTD4, and LTE4 [109,110]. Some investigators theorize that the increase in the cysteinyl leukotrienes, which are known to have a pathogenic role in asthma, may be critical in producing AIA [111]. Inhaled PGE2 attenuated the decrease in pulmonary function that occurs when subjects with AIA are challenged with inhaled lysine acetylsalicylate and also decreased urinary LTE4 excretion, a marker of LTC4 synthase activity [64]. In vitro assays confirm this protective effect of PGE2 in AIA. Although there was no difference in the production of cysteinyl leukotriene in peripheral blood leukocytes among subjects with AIA and either asthmatics who were tolerant of asthma or nonasthmatic controls, the peripheral leukocytes from the subjects with AIA had a significant increase in cysteinyl leukotrienes after aspirin stimulation [112]. When PGE2 was added to the aspirin-stimulated cells from the subjects with AIA, there was a significant decrease in cysteinyl leukotriene levels [112]. This finding suggests that PGE2 has a significant inhibitory effect on the production of cysteinyl leukotrienes in patients with AIA. Studies in which subjects with AIA do not develop bronchospasm after taking selective COX-2 inhibitors suggest that COX-1 inhibition may be critical for aspirin intolerance [108]. A COX-1 product (possibly PGE2) may be critical in restraining the activation of cells that are responsible for the overproduction of bronchoconstrictor leukotrienes.

Summary The relative ineffectiveness of nonspecific COX inhibitors, such as indomethacin, on asthma has led many investigators to dismiss the potential importance of prostanoids as inflammatory mediators and modulators of asthma. That conclusion may be premature, because the acute global blockade of COX may be of too brief to show effects, and the indiscriminate blockade of COX may result in the loss of the effects of potentially ameliorative prostaglandins, such as PGE2. The discovery of a second inducible COX enzyme, COX-2, and the development of selective inhibitors has revealed a dramatic selectivity in the pathophysiology of

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AIA. Selective COX-2 inhibitors have not triggered bronchospasm in patients with AIA, implying that the disease has a precise dependence on COX-1. Similarly, use of a single prostanoid, PGE2, in humans has shown an impressive blockade of allergen-induced mediator release and a blockade of early- and late-phase bronchoconstriction, an outcome shared only by cromoglycate. Because there are at least four distinct receptors for PGE2, which can have opposing effects, a selective EP agonist may be more potent and could represent a new therapy of asthma. Genetic targeting in mice has allowed the selective deletion of a variety of prostanoid receptors, including the PGD2 receptor. In a mouse model of allergic inflammation, loss of the DP receptor rendered mice less susceptible to allergic sensitization. The large quantities of PGD2 released by mast cells makes inhibition of PGD synthase or blockade of one of its two receptors an attractive therapeutic possibility. The effects of COX-2 inhibition in the allergic mouse model revealed increased allergic sensitization and inflammation. Comparable human studies are not available, in part because they would entail continuous use of COX inhibitors from birth. The availability of specific COX-2 inhibitors will allow investigations to find the source of prostanoids that are released after allergic stimuli in humans. As the use of COX-2 inhibitors increase, the long-term effects of these drugs in allergic asthma will have to be investigated. Studies of individual prostanoids and individual prostanoid receptors, together with the use of selective COX inhibitors, and selective inhibitors of endoperoxide synthases have revealed their important effects in asthma. As knowledge of prostanoid action improves, compounds targeting individual prostanoid actions may prove to be helpful in asthma treatment.

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