prostaglandin-d2 and Eosinophilia

The relationship between rhinitis and chronic sinusitis is close and complex and may perhaps show many points of view, anatomical and physiological, epidemiological (by comparing the prevalence of an ailment in carriers of another ailment), experimental (by making nasal allergen provocation tests and studying the sinus anomalies induced) and physiopathological (by phenotyping and comparison of the inflammation present with one another and other ailments). If the results of these studies are convincing, there is still lack of formal proof that confirms the fundamental role of nasal inflammation in general and in particular allergic inflammation in the genesis of sinusitis.

Topics: Allergens; Chronic Disease; Cytokines; Eosinophilia; Humans; Leukocytes; Nasal Mucosa; Nasal Polyps; Nasal Provocation Tests; Paranasal Sinuses; Prevalence; Prostaglandin D2; Radiography; Respiratory Hypersensitivity; Rhinitis; Sinusitis

Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD).. We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD.. Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation.. Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells.. Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Topics: Adult; Aged; Asthma, Aspirin-Induced; Cells, Cultured; Cytokines; Eosinophilia; Female; Humans; Leukocyte Count; Male; Mast Cells; Middle Aged; Nasal Polyps; Prostaglandin D2; Prostaglandins D; Rhinitis; Sinusitis; Thymic Stromal Lymphopoietin; Young Adult

Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ(12) -PGJ2 , a plasma metabolite of PGD2 , on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2 -CRTH2 signals play major roles by reducing eosinophil responses to PGD2 .

Topics: Cell Movement; Chemokine CCL11; Chemotaxis, Leukocyte; Cyclooxygenase Inhibitors; Desensitization, Immunologic; Down-Regulation; Eosinophilia; Eosinophils; Folliculitis; Humans; Indomethacin; Intramolecular Oxidoreductases; Lipocalins; Prostaglandin D2; Receptors, CCR3; Receptors, Immunologic; Receptors, Prostaglandin; Skin Diseases, Vesiculobullous

Chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH2) is a PGD2 receptor found on eosinophils, basophils, and Th2 type T cells which exhibits chemotaxis and functions in activation cascades. However, while a number of CRTH2 antagonists, including ramatroban, are known to exert activity in certain animal models, activity in a guinea pig model of EA-induced airway hyperresponsiveness has not been demonstrated. The newly developed CRTH2 antagonist ASP5642 has shown antagonistic activity against human and guinea pig CRTH2 in previous studies and has also been found effective in treating guinea pig models of airway inflammation and airway hyperresponsiveness. While previous studies have used animals such as rats and mice to evaluate CRTH2 antagonist effects, ours is the first attempt to evaluate CRTH2 function in a guinea pig asthma model, which may prove useful in evaluating the compound's effects in humans, given the comparable airway function between the two species taken together, these data from the present study strongly suggest the utility of ASP5642 in investigating the role of CRTH2 in inflammatory responses and as a drug treatment for human asthma.

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Antigens; Benzhydryl Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbazoles; Cell Count; Eosinophilia; Guinea Pigs; HEK293 Cells; Humans; K562 Cells; Male; Ovalbumin; Pneumonia; Prostaglandin D2; Pyridazines; Receptors, Immunologic; Receptors, Prostaglandin; Sulfonamides

D prostanoid receptor 2 (DP₂) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D₂ (PGD₂). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [³H]PGD₂ from human recombinant DP₂ (K(i) = 0.013 μM), rat recombinant DP₂ (K(i) = 0.003 μM), and human native DP₂ (Th2 cell membranes; K(i) = 0.004 μM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E₁₋₄ receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC₅₀ = 0.028 μM) of human Th2 lymphocytes and cytokine production (IC₅₀ = 0.019 μM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD₂ in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂) in this species (ED₅₀ = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD₂ in guinea pigs (ED₅₀ = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP₂ antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.

Topics: Animals; Apoptosis; Arachidonic Acids; Binding, Competitive; Calcium Signaling; Cell Membrane; Cell Shape; Chemokine CCL11; Chemotaxis; CHO Cells; Complement C5a; Cricetinae; Culture Media, Conditioned; Eosinophilia; Eosinophils; Guinea Pigs; Humans; Indoleacetic Acids; Interleukin-13; Interleukin-5; Leukotriene B4; Lymphocyte Activation; Mast Cells; Prostaglandin Antagonists; Prostaglandin D2; Pulmonary Eosinophilia; Quinolines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Immunologic; Receptors, Prostaglandin; Recombinant Proteins; Th2 Cells; Transfection

We evaluate the immunomodulation of Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists 15d-PGJ(2) and rosiglitazone (RGZ) in a model of chronic eosinophilia. 15d-PGJ(2) and RGZ significantly reduce eosinophil migration into the peritoneal cavity and down-regulate the eosinopoiesis. The synthesis of IL-5 was decreased after the treatment with 15d-PGJ(2) and RGZ corroborating with the eosinophil migration inhibition. However, IgE was decreased only after the administration of 15d-PGJ(2) in part due to B-cell inhibition. We also observed a decrease in the synthesis of IL-33, IL-17 and IL-23, suggesting that besides the modulation of Th2 pattern, there is a modulation via IL-23 and IL-17 suggesting a role of these cytokines in the eosinophil recruitment. In fact IL-17(-/-) mice failed to develop an eosinophilic response. Altogether, the results showed that PPAR-γ agonists mainly 15d-PGJ(2), have therapeutic efficacy in eosinophil-induced diseases with an alternative mechanism of control, via IL-23/IL-17 and IL-33.

Topics: Allergens; Animals; Cell Movement; Cell Proliferation; Disease Models, Animal; Eosinophilia; Eosinophils; Flow Cytometry; Immunoglobulin E; Inflammation; Interleukins; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; Prostaglandin D2; Rosiglitazone; Thiazolidinediones

Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF.. To determine the involvement of PGs in the pathogenesis of EPF.. We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD(2) on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor.. Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD(2) was produced in the lesions. In addition, PGD(2) and its immediate metabolite 15-deoxy-Δ 12,14-PGJ(2) (15d-PGJ(2)) induced sebocytes to produce eotaxin-3 via peroxisome proliferator-activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions.. The PGD(2)/PGJ(2)-peroxisome proliferator-activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF.

Topics: Anilides; Carbazoles; Cell Line; Cells, Cultured; Chemokine CCL26; Chemokines, CC; Eosinophilia; Eosinophils; Fibroblasts; Folliculitis; Humans; Hydantoins; Keratinocytes; PPAR gamma; Prostaglandin D2; Receptors, Prostaglandin; RNA, Messenger; RNA, Small Interfering; Sebaceous Glands; Skin Diseases, Vesiculobullous; Sulfonamides; Transfection

Although it has been suggested that prostaglandin (PG) D(2) is involved in the pathogenesis of allergic rhinitis, whether the inhibition of hematopoietic PGD(2) synthase (H-PGDS) shows beneficial effects on allergic rhinitis has been unclear. We evaluated the effects of a selective H-PGDS inhibitor, TFC-007, on nasal symptoms on Japanese cedar pollen-induced allergic rhinitis of guinea pigs. Sensitized animals were challenged with the pollen once a week. TFC-007 (30mg/kg, p.o.) given once before a challenge almost completely suppressed PGD(2) production in the nasal tissue early and late after the challenge. Although pre-treatment did not affect the incidences of sneezing and early phase nasal blockage, late phase nasal blockage was partially but significantly attenuated; however, nasal eosinophilia was not suppressed. In contrast, when TFC-007 was given once 1.5h after the challenge, the late phase response was not affected. Collectively, PGD(2) produced by H-PGDS early after an antigen challenge can participate in the induction of late phase nasal blockage, although the mechanism may be independent of eosinophil infilatration. The strategy for H-PGDS inhibition may be beneficial for allergic rhinitis therapy.

Topics: Allergens; Animals; Cryptomeria; Enzyme Assays; Eosinophilia; Eosinophils; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Morpholines; Nasal Lavage Fluid; Nasal Obstruction; Pollen; Prostaglandin D2; Pyrimidines; Rhinitis, Allergic, Seasonal; Sneezing

Prostaglandin D2 (PGD2) regulates various immunological responses via two distinct PGD2 receptors, prostaglandin D receptor (DP), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Recent studies have demonstrated that PGD2 induces the migration of eosinophils through CRTH2. Although human eosinophils express both DP and CRTH2, it is unclear whether the function of DP is involved in eosinophil migration.. In this study, we investigated the roles of DP and CRTH2 in eosinophil migration by using selective agonists and antagonists.. Eosinophils were isolated from human subjects with mild eosinophilia by modified CD16-negative selection. After stimulation with or without DP receptor agonist, eosinophil migration was measured by Boyden chamber. The effect of DP agonists on CRTH2-induced eosinophil migration was studied in terms of CRTH2 expression, Ca2+ mobilization, ERK/MAPK phosphorylation, and cyclic AMP (cAMP) production.. Treatment with DP agonists inhibited CRTH2-induced chemotaxis of eosinophils. Furthermore, we showed that DP agonists enhanced cAMP production in CRTH2 agonist stimulation without increasing CRTH2 expression. DP mediates eosinophils through the elevation of intracellular cAMP production but does not change CRTH2 expression.. Taken together, the balance between DP and CRTH2 could influence the degree of PGD2-induced eosinophil migration and DP agonist might regulate eosinophil activation.

Topics: Blotting, Western; Calcium; Cells, Cultured; Chemotaxis; Cyclic AMP; Eosinophilia; Eosinophils; Humans; Hypersensitivity; Inflammation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Th2 Cells

Eosinophilic pustular folliculitis is an inflammatory skin disease characterized by pruritic follicular papulopustules. It is usually resistant to topical and/or systemic corticosteroids, but it responds well to systemic indomethacin. We report here two patients with classical-type disease who were treated with systemic indomethacin. As indomethacin is an inhibitor of cyclo-oxygenases and a potent agonist of the prostaglandin D2 (PGD2) receptor, CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells), we investigated the effects of indomethacin on CRTH2 expression by leukocytes. CRTH2 was expressed on blood eosinophils and lymphocytes. In vitro treatment with indomethacin suppressed the expression of CRTH2 on these cells. In addition, systemic treatment with indomethacin reduced eosinophil CRTH2 expression in another patient in association with improvement of skin lesions and blood eosinophilia. A number of inflammatory cells expressed haematopoietic PGD synthase, an essential enzyme for generating PGD2 in skin lesions of eosinophilic pustular folliculitis. A PGD2-CRTH2 interaction may be involved in the pathogenesis. Moreover, indomethacin may exert its therapeutic effect via reducing CRTH2 expression, as well as by inhibiting PGD2 synthesis.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Down-Regulation; Eosinophilia; Eosinophils; Female; Folliculitis; Humans; Indomethacin; Lymphocytes; Male; Middle Aged; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Recurrence; Suppuration; Treatment Outcome; Young Adult

Prostaglandin D(2) (PGD(2)) has been shown to cause eosinophil, basophil and Th2 cell chemotaxis in vitro and in vivo through an action on the prostaglandin CRTH2 receptor. In the present study, the dependence of PGD(2)-induced eosinophil accumulation in vivo on interleukin-5 (IL-5) blood eosinophilia was investigated.. Guinea-pigs were exposed to aerosols of 13,14di-hydro 15-keto PGD(2) (DK-PGD(2)) or platelet activating factor (PAF) and the eosinophil content of the bronchoalveolar lavage fluid or blood determined. In some experiments, DK-PGD(2) was administered systemically and eosinophilia measured.. Aerosols of DK-PGD(2) caused eosinophil accumulation in the lungs 24h after exposure. DK-PGD(2) (10 microg x ml(-1)) -induced airway eosinophilia was inhibited when animals were treated with the CRTH2 receptor antagonist ramatroban. 1-4h after exposure to DK-PGD(2) a significant decrease in blood eosinophil count was measured. The anti-IL-5 antibody TRFK-5 had no inhibitory effect of DK-PGD(2)-induced airway eosinophilia, but abolished airway eosinophilia induced by exposure of guinea-pigs to aerosols of PAF. Intracardiac injection of DK-PGD(2) induced a dose-related increase in blood eosinophil numbers.. It is concluded that, in the guinea-pig, DK-PGD(2)-induced airway eosinophilia is mediated by an action on prostaglandin CRTH2 receptors and that this response appears to be independent of IL-5.

Topics: Animals; Carbazoles; Eosinophilia; Female; Guinea Pigs; Humans; Interleukin-5; Lung; Platelet Aggregation Inhibitors; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Sulfonamides

Hepatocyte growth factor (HGF) is known to influence a number of cell types, and regulate various biologic activities including cell migration, proliferation, and survival. In a recent study, we found that, in vivo, HGF suppresses allergic airway inflammation, i.e. the infiltration of inflammatory cells including eosinophils into the airway, and further, that HGF reduces Th2 cytokine levels; however, the directly physiologic role of HGF with eosinophils remains unclear. In this study, we investigate the potential of recombinant HGF to regulate the factor-induced chemotaxis of human eosinophils.. Eosinophils were isolated from subjects with mild eosinophilia by modified CD16-negative selection. After culture with or without recombinant HGF, esoinophil chemotaxis was measured by Boyden chamber and KK chamber.. Treatment with HGF prevented eotaxin or prostaglandin D(2) (PGD(2))-induced chemotaxis of eosinophils. Moreover, we demonstrated that extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinases as well as the enhancement of Ca(2+) influx, which are indispensable for eosinophil chemotaxis, were attenuated by HGF treatment.. Taken together, these data suggest that in allergic diseases, HGF not only mediates eosinophils through the inhibition of Th2 cytokines, but also regulates the function of eosinophils directly, provides further insight into the cellular and molecular pathogenesis of allergic reactions.

Topics: Calcium; Cells, Cultured; Chemokine CCL11; Chemokines, CC; Chemotaxis; Eosinophilia; Eosinophils; Hepatocyte Growth Factor; Humans; Prostaglandin D2; Receptors, CCR3; Receptors, Chemokine; Receptors, Immunologic; Receptors, Prostaglandin; Recombinant Proteins

Allergic pathologies are often associated with IgE production, mast cell activation, and eosinophilia. PGD2 is the major eicosanoid, among several inflammatory mediators, released by mast cells. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2, endowed with antagonistic properties. In humans, DP2 is preferentially expressed on type 2 lymphocytes, eosinophils, and basophils and mediates chemotaxis in vitro. Although not yet supported by in vivo studies, DP2 is thought to be important in the promotion of Th2-related inflammation. Herein, we demonstrate that mouse eosinophils express both DP1 and DP2 and that PGD2 exerts in vitro chemotactic effects on eosinophils through DP2 activation. Furthermore, 13,14-dihydro-15-keto-PGD2, a specific DP2 agonist not only increases eosinophil recruitment at inflammatory sites but also the pathology in two in vivo models of allergic inflammation: atopic dermatitis and allergic asthma. By contrast, DP1 activation tends to ameliorate the pathology in asthma. Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy.

Topics: Animals; Asthma; Base Sequence; Chemotaxis, Leukocyte; Dermatitis, Atopic; DNA; Eosinophilia; Eosinophils; Female; Gene Expression; Humans; Hypersensitivity; In Vitro Techniques; Inflammation; Mice; Mice, Inbred BALB C; Mice, Transgenic; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger

PGs play key regulatory roles in inflammation and immunity. PGD2, released from mast cells and Th2 cells during allergic responses, has recently been shown to target a novel receptor, chemoattractant receptor-homologous molecule expressed TH2 cells (CRTH2), in addition to the classic PGD (DP) receptor. CRTH2 is expressed on Th2 cells and eosinophils and mediates chemotaxis of these cells to PGD2. Thus, CRTH2 is thought to be a key receptor mediating eosinophil and Th2 cell recruitment during allergic responses. To examine the role of CRTH2 in this context in vivo, we generated CRTH2 knockout mice. Surprisingly, in an allergic inflammatory model of asthma, CRTH2 knockout mice showed enhanced eosinophil recruitment into the lung compared with wild-type littermate mice. This is consistent with our observation that CRTH2 knockout cells produce significantly higher amounts of IL-5 and IL-3 in vitro. These results suggest a nonredundant role of CRTH2 in restricting eosinophilia and allergic response in vivo.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemotaxis, Leukocyte; Down-Regulation; Eosinophilia; Eosinophils; Female; Interleukin-5; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Th2 Cells; Up-Regulation

We cloned, expressed, and characterized in vitro and in vivo the gene encoding the rat ortholog of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a G protein-coupled receptor for prostaglandin D2 (PGD2). Quantitative reverse transcription-polymerase chain reaction analysis demonstrated highest CRTH2 expression in the lung, brain, ovary, and spleen. Pharmacologically, rat CRTH2 stably transfected in mouse preB lymphoma L1.2 cells behaved very similar compared with the mouse and human orthologs, showing a binding affinity for PGD2 of 11 nM, a functional calcium mobilization when exposed to agonist, and similar sensitivity to agonists and antagonists. In vivo, selective activation of CRTH2 by 13,14-dihydro-15-keto (DK)-PGD2 injection into rats led to a dose- and time-dependent increase of the number of leukocytes in the peripheral blood. Specifically, eosinophils, lymphocytes, and neutrophils were recruited with maximum effects seen 60 min after the injection of 300 microg of DK-PGD2 per rat. Pretreatment of the animals with the CRTH2/thromboxane A2 receptor antagonist, ramatroban, completely abrogated DK-PGD2-induced eosinophilia, suggesting that CRTH2 might have a physiological and/or pathophysiological role in controlling leukocyte migration.

Topics: Amino Acid Sequence; Animals; Base Sequence; Bone Marrow; Carbazoles; Cloning, Molecular; Eosinophilia; Humans; Leukocyte Count; Leukocytes; Mice; Molecular Sequence Data; Prostaglandin D2; Rats; Rats, Wistar; Receptors, Immunologic; Receptors, Prostaglandin; Sequence Homology, Amino Acid; Sulfonamides; Th2 Cells

Prostaglandin D2 (PGD2), the major product of arachidonic acid metabolism via the cyclooxygenase pathway in most mast cells, is present in the airways of atopic asthmatic patients after antigen challenge. Because eosinophilia is characteristic of asthma, we asked whether PGD2 causes eosinophils to accumulate in the airways in vivo. Using an endotracheal tube with two inflatable balloons we isolated a segment of trachea in four anesthetized mechanically ventilated dogs, and we superfused this segment with either a control solution (Hanks' balanced salt solution and antibiotics) or solution containing PGD2 (10(-6) M). Total and differential cell counts were determined at base line and every hour for 4 h during the study. PGD2 caused eosinophil accumulation in the trachea [7.0 +/- 3.4, 28.7 +/- 17.8, 33.7 +/- 13.6, and 35.4 +/- 10.7 (SD) cells/cm2 trachea after 1, 2, 3, and 4 h, respectively, P less than 0.05 vs. controls] but had no significant effect on neutrophil accumulation. The effect of PGD2 on eosinophil accumulation was significantly inhibited by the prostaglandin receptor antagonist SKF 88046 (5 mg/kg iv). We conclude that PGD2 is a selective stimulus that causes accumulation of eosinophils in the tracheal lumen of dogs in vivo.

Topics: Animals; Cell Count; Cell Movement; Dogs; Eosinophilia; Prostaglandin D2; Receptors, Prostaglandin; Sulfonamides; Trachea