Pronounced Eosinophilic Lung Inflammation and Th2 Cytokine Release in Human Lipocalin-Type Prostaglandin D Synthase Transgenic Mice

Abstract

PGD2 is a major lipid mediator released from mast cells, but little is known about its role in the development of allergic reactions. We used transgenic (TG) mice overexpressing human lipocalin-type PGD synthase to examine the effect of overproduction of PGD2 in an OVA-induced murine asthma model. The sensitization of wild-type (WT) and TG mice was similar as judged by the content of OVA-specific IgE. After OVA challenge, PGD2, but not PGE2, substantially increased in the lungs of WT and TG mice with greater PGD2 increment in TG mice compared with WT mice. The numbers of eosinophils and lymphocytes in the bronchoalveolar lavage (BAL) fluid were significantly greater in TG mice than in WT mice on days 1 and 3 post-OVA challenge, whereas the numbers of macrophages and neutrophils were the same in both WT and TG mice. The levels of IL-4, IL-5, and eotaxin in BAL fluid were also significantly higher in TG mice than in WT mice, although the level of IFN-γ in the BAL fluid of TG mice was decreased compared with that in WT mice. Furthermore, lymphocytes isolated from the lungs of TG mice secreted less IFN-γ than those from WT mice, whereas IL-4 production was unchanged between WT and TG mice. Thus, overproduction of PGD2 caused an increase in the levels of Th2 cytokines and a chemokine, accompanied by the enhanced accumulation of eosinophils and lymphocytes in the lung. These results indicate that PGD2 plays an important role in late phase allergic reactions in the pathophysiology of bronchial asthma.

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

“…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].…”

Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion

“…In addition, PGD 2 also possesses effector functions during inflammation. For instance, the production of PGD 2 by allergen-activated mast cells and possibly by Agchallenged Th2 lymphocytes is involved in allergic reactions that develop in the lungs [3][4][5]. On the other hand, PGD 2 also appears to mediate regulatory functions during inflammation for example by down-regulating carrageenin-induced pleurisy and colitis in rats [6][7][8].…”

Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis

“…PGD 2 is a major mast cell mediator released during the allergic response (5), but its ability to induce chemotaxis of eosinophils, basophils, and Th2-type T cells via a novel receptor, CRTH2, has only recently been realized (6,7). 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 (8) and amelioration of lung eosinophilia and airway hyper-reactivity in mice deficient of the classical PGD 2 receptor, DP (9).…”