Cell therapy by manipulation of biological function of prostaglandin as self-defense factor

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Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme to produce prostaglandin (PG) D and J series. These PGs are involved in inflammation and immune system. While PGD_2 mediates sleep and allergic reaction in asthma, the non-enzymatic metabolite, 15-deoxy-Δ^<12,14>-PGJ_2, displays several anti-inflammatory effects. Since the PGs are structurally labile and instable in body, constitutive expression of the producing enzyme, PGDS would be expected to evaluate biological activities of PGD2 and PGJ series. To determine whether introduction of PGDS exerts proinflammatory or anti-inflammatory effect, human hematopoietic PGDS complementary DNA-expressing retrovirally transfected fibroblasts were introduced in vivo, and effects of the introduction on several inflammatory models were investigated. Introduction of PGDS-expressing fibroblasts effectively attenuated carrageenin-induced paw edema as an acute inflammatory model and formation of granuloma and angiogenesis in sponge-implanted … More model as a chronic inflammatory model, suggesting the introduction could be anti-inflammatory. Moreover, expression of PGDS decreased generation of chemokines followed by decreased infiltration of leukocytes in sodium urate monohydrate crystal-induced acute inflammation using air-pouch model in mice, and suppressed fibrosis with reduced expression of cytokines and growth factors in bleomycin-induced lung injury and bleomycin-induced skin sclerosis. Furthermore, elevated pressure in right atrium was attenuated by introducing PGDS-expressing fibroblasts in monocrotaline-induced pulmonary hypertension. Administration of 15-deoxy-Δ12,14_prostaglandin J2 also reduced deterioration of lunge fibrosis and skin sclerosis in the models. Therefore, a part of the preventive action of PGDS-expressing fibroblasts raise could be mediated via biological activities by 15-deoxy-Δ^<12,14>-prostaglandin J_2. These results suggest a potential cell therapy for such pathogenesis by PGDS-expressing cells and the possibility of therapeutic approaches targeting for PGD_2-derived metabolites. Less