Aspirin Intolerance: Experimental Models for Bed-to-Bench

Yamashita, Masamichi

Liu et al. [63] studied mice with knockout of microsomal PGE synthase-1 (mPGES-1), which associates with COX-2 and metabolizes PGH 2 to PGE 2 (Fig. 2) . After pretreatment with dust mite extract and challenge with lysine-aspirin (1.2 mg/12 µL via a ventilator), there was a marked increase of respiratory tract resistance and elevation of the levels of cysLTs, histamine, and MCP-1 (an indicator of mast cell degranulation) in bronchoalveolar lavage fluid. Ketorolac (a selective COX-1 inhibitor) and celecoxib (a selective COX-2 inhibitor) failed to increase respiratory tract resistance in this model. However, an EP2 receptor agonist significantly inhibited these responses, and EP2 receptor knockout mice showed smaller increases than mPGES-1 knockout mice. They recently observed that interleukin (IL)-33, a type 2 helper T (Th2) cytokine released from necrotic cells as "alarmin" [64] , was highly expressed in the lung epithelium of mPGES-1 knockout mice pretreated with mite extract and in the nasal polyps of AERD patients [65, 66] . It was reported that IL-33 is produced by mast cells and that it increases the production of IL-4, IL-5, and IL-6 by bone marrow-derived murine mast cells and a murine mast cell line (MC/9) when these cells received IgE sensitization followed by antigen treatment. It was also reported that the IL-33 receptor (ST-2) is expressed by mast cells after atopic stimulation [67] .