Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention

Prostaglandin D_2 Augments Low-dose Antigen-induced Th2 Type Airway Inflammation in Mice

Prostaglandin D_2 (PGD_2), a mast cell-derived lipid mediator is detected in lage amounts in airways of asthmatics, but its role of largely unkown. To clarify the role of PGD_2 in Th2-type airway inflammation which characterizes asthma, we studied the effects of aerosolized PGD_2 on the inflammatory response to a low-dose antien challenge in airways of mice. Mice sensitized with ovalbumin (OVA) were challenged with a conventional-dose (1%) or a low dose (0.1%) aerosolized OVA. Mice received low - dose OVA challenge were pretreated with aerosolized PGD_2 (10^M) (PGD_2 plus low-dose OVA mice) or saline (low-dose OVA alone mice) 24 hrs before the OVA challenge. Some mice were pretreated with PGD_2 but challenged with saline (PGD_2 alone mice). Airway inflammation was evaluated by the numbers of eosinophils, lymphocytes and macrophages in bronchoalveolar lavage fluid. The degree of airway inflammation in the PGD_2 alone mice and the low-dose OVA alone mice were only marginal. However, the PGD_2 plus low-dose OVA mice displayed a similar degree of airway inflammation with mice received conventional-dose OVA challenge. Levels of interleukin (IL)-4 and IL-5 were significantly increased in the PGD_2 plus low-dose OVA mice than the low-dose OVA alone mice. PGD_2 (10^-10^ M) did not affect the Th2-type cytokine production by OVA specific T cells in response to OVA stimulation in vitro. Immunohistochemical analysis of lung tissue revealed that airway epithelium of the PGD_2 plus low-dose OVA alone mice were strongly stained with monoclonal antibody against macrophage-derived chemokine (MDC), a Th2 cell-specific chemokine. These results suggest that PGD_2 augments Th2 cell -type airway inflammation via epithelial experssion of MDC