Effects of Prostaglandin D2, 15-Deoxy-Δ12,14-prostaglandin J2, and Selective DP1 and DP2 Receptor Agonists on Pulmonary Infiltration of Eosinophils in Brown Norway Rats

Abstract

Prostaglandin (PG) D 2 is an arachidonic acid metabolite that is released by allergen-stimulated mast cells. It is a potent in vitro chemoattractant for human eosinophils, acting through the DP 2 receptor/chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Furthermore, there is in vivo evidence that PGD 2 contributes to allergen-induced pulmonary eosinophilia via its classic DP 1 receptor. The PGD 2 -derived product 15-deoxy-⌬ 12,14 -PGJ 2 is widely used as a peroxisome proliferator-activated receptor ␥ agonist and has been shown to have anti-inflammatory properties. However, this substance can also activate eosinophils in vitro through the DP 2 receptor. The objectives of the present study were to determine whether PGD 2 and 15-deoxy-⌬ 12,14 -PGJ 2 can induce pulmonary eosinophilia, and, if so, to examine the abilities of selective DP 1 and DP 2 receptor agonists to induce this response. Brown Norway rats were treated by intratracheal instillation of PGs. Vehicle and 5-oxo-6,8,11,14-eicosatetraenoic acid were used as negative and positive controls, respectively. Lung eosinophils were identified by immunostaining of lung sections with an antibody to major basic protein. Both PGD 2 and 15-deoxy-⌬ 12,14 -PGJ 2 induced robust eosinophilic responses that were apparent by 12 h and persisted for at least 48 h. Two selective DP 2 receptor agonists, 15R-methyl-PGD 2 and 13-14-dihydro-15-keto-PGD 2 , induced similar responses, the former being more potent than PGD 2 , whereas the latter was less potent. The selective DP 1 receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] was completely inactive. We conclude that PGD 2 and 15-deoxy-⌬ 12,14 -PGJ 2 induce eosinophil infiltration into the lungs through the DP 2 receptor. The potent in vitro DP 2 receptor agonist 15R-methyl-PGD 2 is also very active in vivo and should be a useful tool in examining the role of this receptor.Prostaglandin (PG) D 2 is a metabolite of arachidonic acid that is formed by the action of PGD synthase on the cyclooxygenase product PGH 2 . There are two enzymes that catalyze this reaction: lipocalin-type PGD synthase, which is found in the central nervous system and hematopoietic PGD synthase, which is present in antigen-presenting cells, mast cells (Urade and Hayaishi, 2000), and Th2 cells . The association of PGD 2 with mast cells has focused attention on its possible role in asthma and other allergic diseases. High levels of this prostaglandin are rapidly released into the airways after allergen challenge of asthmatic human subjects (Murray et al., 1986).The recent finding by Narumiya's group that disruption of the classic G s -coupled (DP 1 ) receptor for PGD 2 protects mice against asthma-like responses after antigen challenge (Matsuoka et al., 2000) has provoked considerable interest in the role of PGD 2 in this disease. Mice lacking this receptor exhibit reduced pulmonary eosinophilia, hyperresponsiveness, and Th2 cytokine levels in response to antigen...

Cutting Edge: Prostaglandin D2 Enhances Leukotriene C4 Synthesis by Eosinophils during Allergic Inflammation: Synergistic In Vivo Role of Endogenous Eotaxin

“…To this end, we first developed a mouse model of PGD 2 -induced eosinophilia. Similar to other models (10,12), administration of PGD 2 in naive mice did not elicit eosinophil migration (Fig. 1A).…”

“…PGD 2 -induced pleural eosinophilia in sensitized mice was apparent within 6 h, reached maximum levels within 24 h, and was not associated with an influx of neutrophils or mononuclear cells (data not shown). It is noteworthy that PGD 2 's ability to induce local eosinophilia had already been shown in other models of inflammation, which used different strategies to create a proper PGD 2 -sensitive environment (10,12,19). The mechanism involved in the PGD 2 responsiveness acquired after sensitization has not been characterized but may involve differential expression of PGD 2 receptors.…”

Hierarchy of eosinophil chemoattractants: role of p38 mitogen‐activated protein kinase

“…Therefore, the primary role of PGD 2 released by activated mast cells [7] might be to initiate the evasion of eosinophils from the blood and, at the same time, enhance their responsiveness to other chemoattractants that the eosinophils will consecutively encounter in the tissue. Among these might be 5-oxo-ETE, which is released from other infiltrating leukocytes, such as monocytes, macrophages, dendritic cells, lymphocytes or neutrophils [11,18,19,37,38]. 5-oxo-ETE and eotaxin have limited efficacy in blood.…”

“…Besides chemotaxis, we have shown that activation of CRTH2 also causes eosinophil respiratory burst and the release of eosinophils from the bone marrow [10]. In vivo, PGD 2 can induce pulmonary eosinophilia [11], and a significant contribution of PGD 2 to the late phase allergic reaction is suggested by enhanced eosinophilic lung inflammation and cytokine release in transgenic mice overexpressing PGD 2 synthase [12]. However, eosinophils also express the DP receptor [13], which is a second receptor for PGD 2 , and DPdeficient mice have reduced pulmonary responses to allergen [14].…”

Opposing Immunomodulatory Roles of Prostaglandin D2 during the Progression of Skin Inflammation

“…For example, administration of an H-PGDS inhibitor improved mouse airway inflammation (24). Furthermore, treatment with a CRTH2 agonist aggravated atopic dermatitis and asthma in mice, whereas intratracheal administration of PGD 2 promoted eosinophil migration in rats (25,26). Thus, PGD 2 is likely to regulate inflammation differently, depending on the disease type.…”