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

造血前列腺素D合成酶(PGDS)是合成前列腺素(PG)D和J系列的关键酶。这些PG与炎症和免疫系统有关。当前列腺素D_2介导哮喘的睡眠和过敏反应时，非酶代谢产物15-脱氧-前列腺素D_2(15-deoxy-Δ^&lt；12，14&gt；-PGJ_2)具有多种抗炎作用。由于PGs的结构不稳定，在体内不稳定，产生酶的结构性表达，PGDS有望用于评估PGD2和PGJ系列的生物学活性。为了确定PGDS的导入是否具有促炎或抗炎作用，将表达互补DNA的人造血PGDS逆转录病毒导入成纤维细胞，并观察其对几种炎症模型的影响。导入表达PGDS的成纤维细胞有效地减轻角叉菜胶诱导的足肿胀作为急性炎症模型和海绵植入…中肉芽肿和血管生成的形成更多的模型作为慢性炎症模型，提示引入可能具有抗炎作用。此外，在一水尿酸钠结晶诱导的小鼠急性炎症模型中，PGDS的表达减少了趋化因子的产生，进而减少了白细胞的渗透；在博莱霉素诱导的肺损伤和博莱霉素诱导的皮肤硬化中，PGDS的表达减少了细胞因子和生长因子的表达，从而抑制了纤维化。此外，在野百合碱诱导的肺动脉高压中，通过引入表达PGDS的成纤维细胞可以减轻右心房的压力升高。给予15-脱氧-Δ12，14_前列腺素J2也减轻了模型大鼠急性肺纤维化和皮肤硬化的恶化程度。因此，15-脱氧-Δ；12，14-前列腺素J_2可能通过15-脱氧-前列腺素J_2的生物活性而发挥部分预防作用。这些结果提示，通过表达前列腺素D_2的细胞来治疗这种疾病是一种潜在的细胞疗法，并可能针对前列腺素D_2衍生的代谢物。较少

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